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We get it, learning so many different organic reactions is probably giving you a headache, but hopefully this episode can help! We’re getting even deeper into carboxylic acid derivatives, some of which are used in common headache relieving painkillers. In this episode of Crash Course Organic Chemistry, we’ll learn how to convert more reactive carboxylic acid derivatives into less reactive ones, turn carboxylic acids into acid chlorides, reduce carboxylic acid derivatives using metal hydrides, and more! Plus, we’ll get to add the first stage of synthesizing Penicillin V to our Mold Medicine Map!

Episode Sources:
https://www.worldofmolecules.com/drugs/tylenol.htm
https://cen.acs.org/articles/92/i29/Does-Acetaminophen-Work-Researchers-Still.html
https://pa01000125.schoolwires.net/cms/lib/PA01000125/Centricity/Domain/366/Chap14%20Ester%20Amide.pdf
Gates, M., & Tschudi, G. (1956). The synthesis of morphine. Journal of the American Chemical Society, 78(7), 1380-1393.
Seavill, P. W., & Wilden, J. D. (2020). The preparation and applications of amides using electrosynthesis. Green Chemistry.
Introduction to Organic Chemistry, Brown & Poon, 5th edition.

Series Penicillin References:
Nicolaou, K. C., & Sorensen, E. J. (1996). Classics in total synthesis: targets, strategies, methods. John Wiley & Sons.
Sheehan, J. C. (1982). The enchanted ring: the untold story of penicillin.
Primary literature for Sheehan’s penicillin synthesis: Sheehan, J.C. & Izzo, P.T. J. Am. Chem. Soc. 1948, 70, 1985; Sheehan, J.C. & Izzo, P.T. J. Am. Chem. Soc. 1949, 71, 4059; Sheehan, J.C. & Bose A.K. J. Am. Chem. Soc. 1950, 72, 5158; Sheehan, J.C., Buhle, E.L, Corey E.J., Laubach, G.D. & Ryan J.J. J. Am. Chem. Soc. 1950, 72, 3828; Sheehan, J.C. & Laubach, G.D. J. Am. Chem. Soc. 1951, 73, 4376; Sheehan, J.C. & Hoff, D.R. J. Am. Chem. Soc. 1957, 79, 237; Sheehan, J.C. & Corey E.J. J. Am. Chem. Soc. 1951, 73, 4756

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, 2013.

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

Keeping up with all these reactions might be starting to give you a headache. But don’t worry, the organic chemistry we’re going to learn in this episode can help you with that! We're going to dive deeper into carboxylic acid derivatives, some of which can be used to make Tylenol, also known as acetaminophen or paracetamol.

It's a common product to ease minor aches and pain, but it's a bit of an oddball in the painkiller world. Painkillers usually come in several varieties. Non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, work directly at the site of the pain to stop the formation of compounds that play a big part in pain and inflammation.

On the other hand, opioids, such as morphine and codeine, stop us from sensing pain by blocking pain signals in our nervous system. Acetaminophen doesn’t sit in either of these categories. In fact, even though we know that it does work, and we have some solid theories about how it might work, the exact details are still a bit of a collective medical shrug.

We do know a few different ways to make acetaminophen, though. One is how it was identified in 1893: in the urine of patients taking another painkiller, phenacetin. But another, less gross way is starting with p-aminophenol and acetic anhydride, which contains the anhydride functional group.

In this episode we’ll talk more about this carboxylic acid derivative and others, and how we can convert between them – making a medicine or two along the way! [Theme Music]. We’ve met four carboxylic acid derivatives in the past few episodes: acid chlorides, anhydrides, esters, and amides. In episode 31, we talked about how they react with nucleophiles or can be hydrolyzed, but we can also interconvert between them!

There's one key rule: we can only easily convert one derivative to a less-reactive derivative. So, for example, we can convert an acid chloride to an ester, but we can’t directly convert an amide to an ester. And I say "directly" because there is a roundabout way we can convert an amide to its more-reactive friends... by turning the amide back into a carboxylic acid.

Then, we can react the carboxylic acid with phosphorus pentachloride or thionyl chloride to get an acid chloride – like we did in episode 30. And from there, there are lots of possibilities. As you might remember, acid chlorides are the most reactive of our barbershop quartet of carboxylic acid derivatives.

So they can be converted to any of the other three derivatives. The easiest way to convert them into anhydrides, the second most reactive derivative, is to react them with a carboxylic acid salt. This reaction can also be done with a plain old carboxylic acid if you also add pyridine, a base that deprotonates the carboxylic acid and makes a carboxylate salt in our reaction flask.

So I guess what I'm saying here is: you're going to eventually need a carboxylic acid salt to do this reaction. For example, this reaction produces acetic anhydride, which is an example of a symmetrical anhydride, where the group attached to each of the carbonyl carbons is the same. We can also make mixed anhydrides, where the two groups attached to the carbonyl carbons are different.

If the name only has two parts, like acetic anhydride, you know it’s symmetrical. If the name has three parts, like acetic butyric anhydride, you know it’s mixed. By the way, anhydride naming is one of the places where IUPAC lets some common names slide.

At the beginning of this episode, I mentioned that acetic anhydride is one of our Tylenol precursors. But it's also a compound that can be used to make aspirin, another common painkiller, which happens to contain an ester – the next most reactive of our carboxylic acid derivatives. To do that, we react acetic anhydride with salicylic acid, a compound originally extracted from willow tree bark.

In fact, we can turn any anhydride into an ester by reacting it with an alcohol. The anhydride gets cut down the middle, with one carbonyl group forming the ester and the other departing as a carboxylic acid. Remembering our key rule with these interconversion reactions, we can also convert the more-reactive acid chlorides to less-reactive esters.

To do this, we can use an alcohol and a mild base to swap out the chloride for an ester group. The base neutralizes the hydrochloric acid that forms as a side product. And that brings us to the least reactive of our carboxylic acid derivatives: amides.

Our acid chlorides, anhydrides, and esters can all be transformed into this group. Even though amide groups are the least reactive of this quartet, they're far from useless. They show up in the proteins assembled in your body, the Kevlar in bulletproof vests, and DEET (the most commonly used compound in insect repellents).

About a quarter of all marketed drugs contain an amide group, too –. Penicillin V contains two of them! But we’ll loop back to that in a second.

For now, let's focus on making amides, and we'll start with our most reactive carboxylic acid derivative. We can react acid chloride with ammonia or with a primary or secondary amine to convert it to an amide. Whether we use ammonia or an amine, two equivalents are needed – one to take the place of the chloride, and the other to form a salt with the hydrochloric acid byproduct.

It’s a similar story for converting anhydrides to amides: two equivalents of ammonia or an amine. The only difference here is that a side product forms, which is an ammonium carboxylate salt. And, lastly, to convert esters to amides, we use the same stuff but can get away with using just one equivalent of ammonia or amine.

This is because the hydrogen we lose when the nitrogen takes the oxygen’s place can be picked up by the alkoxide anion that’s kicked out, forming an alcohol. There's no danger of forming wild catalysts like hydrochloric acid here. Okay, now we know how to make amides, we can fill in the very first stage in our Mold Medicine Map.

Yep, it's penicillin V synthesis time! Our map begins with valine, an essential amino acid. The primary amine group in valine is perfect for reaction with an acid chloride – in this case, 2-chloroacetyl chloride.

This reaction forms what will later become one corner of the 4-membered beta-lactam ring (which is just a special type of cyclic amide structure) in the penicillin structure. We also form another amide group a little further in the map. In this case, it’s a reaction between 2-phenoxyacetyl chloride, and a primary amine group jutting off the structure we’ve formed to that point.

You can see that this step gets us quite close to our final penicillin structure – we’ll just need a couple more reactions, and some future episodes, to get us the rest of the way there. Moving the focus away from our Mold Medicine Map and back to our carboxylic acid derivatives, it's also worth mentioning that they have a few useful reactions with organometallic reagents. An interesting one of these is when you mix esters with Grignard reagents.

At first glance, this reaction looks pretty strange. We’ve seen reactions that turn esters into alcohols before, but this transformation from an ester into a tertiary alcohol is a bit different. To understand how it happens, like always, let’s look closer at the mechanism.

In the first step, the alkyl group from our Grignard reagent adds on to the carbonyl carbon. And in the second step, the alkoxide group is eliminated, forming a ketone. Being able to make a ketone from an ester would be great – but sadly, this intermediate is way too reactive for us to isolate it.

This ketone immediately reacts with another equivalent of the Grignard in another addition reaction to form the tertiary alkoxide, which we can treat with acid in a second step to form the alcohol. If we try to mix acid chloride (which is more reactive than esters) with a Grignard reagent, we get a similar reaction with a ketone intermediate that’s tricky to isolate before it reacts further with the Grignard reagent. However, we can get to that elusive ketone if we mix an acid chloride with an organocuprate reagent, known as a Gilman reagent – as we saw in Episode 28.

Remember organocuprates are less reactive compared to Grignards, so organocuprates don’t usually react with the carbonyl of a ketone once it’s formed, so there will be enough time and enough ketone hanging around to isolate it. Now, the final set of carboxylic acid derivative reactions we’ll learn are reductions. And we'll use some reducing agents we’ve already met: metal hydrides. (These aren't organometallic reagents, by the way, because they contain metal but not carbon.) Lithium aluminum hydride can reduce all carboxylic acid derivatives.

Because we can reduce the less-reactive esters, amides, and even carboxylic acids, we rarely bother to make more reactive compounds like acid chlorides and anhydrides to do these reactions. So let's look at the reduction of esters and amides. In these reactions, the hydride ion acts as a nucleophile, attacking the carbonyl carbon in an addition reaction.

This forms a tetrahedral intermediate. For an ester, this tetrahedral intermediate pushes out an alkoxide, forming an aldehyde. Then, another hydride ion attacks, forming a new tetrahedral intermediate.

After all this is done, we can add in a source of protons, like water, and the negatively charged oxygen grabs a hydrogen, giving an alcohol product. So, in the end, we get two separate alcohols when we reduce an ester. Like the ketone in the Grignard reagent reaction, the aldehyde produced partway through this reduction is too reactive to isolate.

But we can make an aldehyde from an ester if we use a different reagent:. Di-iso-butyl-aluminum hydride, or DIBAL-H. And yes the "H" is silent.

DIBAL-H can help us turn esters into aldehydes without taking them all the way to an alcohol, because it forms a stable intermediate after the initial nucleophilic attack of the hydride ion. Specifically, the aluminum forms a bond to the oxygen. This intermediate isn’t reduced further at cold temperatures, but dilution in water collapses it, forming the aldehyde.

And I didn't forget about amides! We can use lithium aluminum hydride to reduce these to amines. Let’s use a specific example to check out the arrow-pushing.

The mechanism for this reduction starts a lot like the one we saw before, with the hydride ion acting as a nucleophile and attacking the carbonyl carbon. Again, we get a tetrahedral intermediate. But then this reaction differs: the oxygen anion bonds with the aluminum, and in the following step it’s removed when the iminium ion is formed.

Another equivalent of the reducing agent can swoop in to complete the reaction and form the amine. At the end of the reaction, we add an alcohol to use up any leftover lithium aluminum hydride hanging around, because it’s super reactive. On a very small scale, you could use water for this – but be careful and follow your risk assessment!

The reaction between water and the reducing agent is very exothermic, so there’s a risk of setting everything on fire! This reaction loops us right back to where we started by discussing painkillers. Amide reduction is a key step in one of the many syntheses of morphine, one of the opioids.

In the synthesis, lithium aluminum hydride is used to convert the tertiary amide group to a tertiary amine, which is actually a featured group in all opioid painkillers. And with that, we've wrapped up our learning about carboxylic acid derivatives, though they're bound to show up later in the course. In this episode, we:.

Saw how to convert more reactive carboxylic acid derivatives into less reactive ones. Remembered how to turn a carboxylic acid into an acid chloride, and. Reduced carboxylic acid derivatives with organometallic reagents and metal hydrides.

In the next episode, we’ll talk about how we can make some parts of molecules react while making sure that other parts don’t. Until then, thanks for watching this episode of Crash Course Organic Chemistry. If you want to help keep all Crash Course free for everybody, forever, you can join our community on Patreon.