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What do the smells of feet, armpits, vomit, and goats all have in common? (Besides being super gross…) Carboxylic acids! Despite being responsible for some of our least favorite odors, carboxylic acids are also super useful in organic chemistry. In this episode of Crash Course Organic Chemistry, we’ll review carboxylic acid synthesis and nomenclature, react carboxylic acids to form salts, esters, and acid chlorides, and start our journey towards synthesizing one of the most important organic chemicals in medicine, penicillin!

Episode Sources:
Kennedy, J: Common names of carboxylic acids https://jameskennedymonash.wordpress.com/2014/11/26/common-names-of-carboxylic-acids/
Thomas, J: Mouldy Mary and the cantaloupe
https://mcdreeamiemusings.com/blog/2019/8/11/1013vvme5498w77bglwoh5ck4exowx
C H Arnaud, C&EN: Penicillin
https://cen.acs.org/articles/83/i25/Penicillin.html

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!

What’s the connection between the smells of feet, underarms, vomit and... goats? Carboxylic acids. The smell of feet is partly due to the presence of isovaleric acid, which is produced by the bacteria living on your foot skin.

Bacteria also turn odorless underarm secretions, such as amino acids, into malodorous molecules, which include carboxylic acids. The stench of vomit is caused by butyric acid, produced by bacteria in our gut. Butyric acid is also found in rancid butter (that's where its name comes from), and it's a key part of the aroma of Parmesan cheese.

It's also added to some brands of American milk chocolate to give a ‘tangy’ flavor. Yes, I basically just said that puke-flavored chocolate exists, and now it's going to haunt me forever. And three carboxylic acids take their common names from the Latin word for goats: caproic acid, caprylic acid and capric acid.

Found in small amounts in goats’ milk, and produced in larger amounts as the milk ages, they contribute to that goaty stench. Given these awful smells, you might wonder why we’d want to work with carboxylic acids at all. But we can actually make some pretty nice-smelling compounds using carboxylic acids as a starting point, and we can convert them into other useful compounds for organic synthesis. [Theme Music].

Let’s kick off by reminding ourselves how we can make a carboxylic acid. For example, we can oxidize alcohols or aldehydes with chromic acid or another suitable oxidizing agent. We can also make them from Grignard reagents.

Reacting the Grignard reagent with carbon dioxide gives a carboxylate salt, which can be protonated with acid to give a carboxylic acid. We can get a more specific name for any carboxylic acid by looking at its structure, using the number of carbons in the longest chain and adding the suffix '-oic acid.' A carboxylic acid with two carbons is ethanoic acid, a carboxylic acid with three carbons is propanoic acid, and so on. So in the previous reaction, we made 2-methylpropanoic acid.

When it comes to naming compounds, carboxylic acids have the highest priority among carbon-containing functional groups. So, say we have a molecule containing both a ketone and a carboxylic acid group, the carboxylic acid forms the base name, we assign the carboxylic acid carbon the number 1, and the ketone gets a prefix. An example of this is 4-oxopentanoic acid, also known as levulinic acid, a compound used as a starting point for the synthesis of some pharmaceuticals and industrial chemicals.

This compound, like many we've mentioned, has a systematic IUPAC name and a common name. Like how ethanoic acid, the acid in vinegar, has the common name acetic acid. And as you’d expect from all these names, carboxylic acids are acidic.

If they have... oh about 4 carbons or fewer, they can dissolve in water. The hydrogen in the -COOH part of the structure will be partially ionized, forming a hydrogen ion and leaving behind a carboxylate ion. Specifically, carboxylic acids are weak acids, because they don’t release hydrogen ions into solution as much as a strong acid like hydrochloric acid does.

The -COOH part of these structures allows inter-molecular hydrogen bonds to form between two acid molecules, or an acid and water. So carboxylic acids have high boiling points, and all of those with fewer than ten carbons in a straight chain are liquids at room temperature. We can react shorter-chain carboxylic acids with sodium or potassium hydroxide to form water-soluble salts too.

The hydroxide ion grabs the proton from the carboxylic acid group, forming water and leaving a carboxylate ion behind. In fact, even weak bases like ammonia can pull off a hydrogen ion and form a carboxylate ion. As we know from earlier episodes, both hydroxide ions and ammonia are good nucleophiles – which actually highlights an issue that can come up in the lab.

Most basic nucleophiles tend to deprotonate carboxylic acids! So, unlike aldehydes and ketones, we can’t just use a nucleophile to add groups to the carbonyl carbon here. We’ll have to get a little more creative with our chemistry.

Before we tackle that problem, though, let’s look at some of the other reactions carboxylic acids can undergo. If we want to get back to an alcohol from a carboxylic acid, we can use a reducing agent such as lithium aluminum hydride. This is a powerful reducing agent, so after the reaction, we add a proton source VERY carefully to react any unreacted lithium aluminum hydride and give our alcohol a proton back.

Another way to remove the carboxylic acid group has a very straightforward name: decarboxylation. This involves heating the carboxylic acid, and replaces the carboxylic acid group with a hydrogen atom. So if we heat the heck out of almost any carboxylic acid, we can get it to decarboxylate.

And this reaction happens really easily when you heat compounds that have a carbonyl group one carbon away from the carboxylic acid group. However, sometimes you don't want to get rid of the carboxylic acid group entirely, so there are also reactions to convert it into other functional groups. In fact, we can freshen up some of those bad-smells by converting carboxylic acids into pleasant-smelling esters by Fischer Esterification.

This is an acid-catalyzed reaction of a carboxylic acid with an alcohol to form an ester. Esters are often key parts of the smells of flowers and fruits, and are commonly used in perfumes. Fischer Esterification can also be classified as a type of condensation reaction, because the two reactants kick out a water molecule when they combine.

To get more specific, first, the carbonyl oxygen grabs a proton from the acid catalyst. Next, the lone pair on the alcohol oxygen acts as a nucleophile, attacking the carbonyl carbon. Another alcohol molecule swoops in, deprotonating the hydrogen from the oxonium ion in that one-two punch of attack-then-deprotonation we’re getting familiar with.

The OH group on the carboxylic acid finds a hydrogen ion from the acid catalyst, which makes water, a good leaving group! With a little help from the neighboring oxygen atom in the molecule, the water leaves. And finally, another alcohol molecule from solution grabs the extra hydrogen on the carbonyl oxygen, giving us an ester as our final product.

All of these steps are reversible, so the product isn’t formed super efficiently. But never fear, le Chatlier is here! We have the power to adjust the equilibrium of chemical reactions.

Specifically, if we remove one of the products along the way, we can push the reaction forward. In a lab, removing the water as it forms using a special piece of equipment increases our yield of the ester. Speaking of tricky lab situations, how about that problem we mentioned earlier – the issue of nucleophiles deprotonating carboxylic acids instead of attacking the carbonyl carbon?

To solve this problem, we can convert the carboxylic acid to a more reactive functional group: an acid chloride, using either phosphorus pentachloride or thionyl chloride. And let's just go with phosphorus pentachloride as our example. The reaction starts when the lone pair of electrons on the carbonyl oxygen forms a bond with the phosphorus atom – with a little help from the other oxygen in the molecule – and kicks a chloride ion off of phosphorous pentachloride.

The chloride ion we kicked out in the previous step swoops back and attacks the carbonyl carbon. Then, a very stable double bond forms between the phosphorus and this oxygen. This double bond is a big part of why this reaction happens this way, just like we saw in the Wittig reaction in Episode 28!

Specifically, with the formation of this bond, we lose chloride as a leaving group, which pulls off the nearby hydrogen to reform our carbon-oxygen double bond. This gives us the acid chloride, with hydrochloric acid and phosphorous oxychloride as the other products. Acid chlorides, along with other carboxylic acid derivatives, are involved in many useful reactions in organic chemistry.

In fact, acid chlorides were used in the synthesis of the first mass-produced antibiotic: penicillin, which is an important carboxylic acid in medicine. Throughout the rest of the Crash Course Organic Chemistry series, we’ll apply many of the reactions we learn to explore the chemical synthesis of penicillin. But penicillin was an accidental discovery – not a medicine dreamed up by humans.

And the story of this compound is much more complicated than just one scientist making a lucky discovery in 1928. Let’s head to the Thought Bubble to learn more. Returning to his lab after a summer holiday, the microbiologist Alexander Fleming discovered that one of his petri dishes of bacteria had been unintentionally left out on a bench.

Spores of a fungus had blown into the lab and contaminated the dish, and the temperatures had been perfect to encourage both the fungus and the bacteria to grow. But wherever the fungus had grown, the bacteria were absent. Fleming realized that the fungus made a chemical compound that killed the bacteria.

The fungus was from the genus Penicillium, so Fleming named this mysterious compound ‘penicillin'. But, despite many attempts, he was unable to isolate it. At Oxford University, a biochemist named Ernst Chain found Fleming’s publication on penicillin, and suggested to his supervisor, Howard Florey, that they try to isolate it.

Penicillin was eventually isolated and purified in 1941. That same year, penicillin was first used to treat an infection in a police officer. It was later hailed as a wonder drug during World War II for its ability to combat infections in wounded troops.

But there was still a huge unsolved problem in the early 1940s: the low yield of penicillin from the mold. But in 1943, a bacteriologist named Mary Hunt made a breakthrough while working at the US Department of Agriculture's Northern Regional Research Laboratory in Peoria, Illinois! Nicknamed ‘Moldy Mary,’ she hunted down moldy fruits and vegetables to test for the presence of penicillin in the lab.

A spoiled cantaloupe melon had a fungus, Penicillium chrysogenum, that produced 200 times more penicillin than the fungus that Fleming stumbled upon, making mass production possible! Thanks, Thought Bubble! Since Mary Hunt's cantaloupe discovery, we've learned a lot more – like, the penicillin are actually a family of compounds, with different potencies and ways to administer the medicine.

The penicillin that Fleming discovered and Chain and Florey isolated (and even won a Nobel Prize for in 1945) was penicillin F. The stuff that was produced from Hunt’s spoiled cantaloupe melon was penicillin G. In later episodes, we’ll be looking at Dr.

John C. Sheehan’s synthesis of penicillin V, which is the first penicillin to be synthesized from scratch instead of extracted from a fungus. This synthesis takes many steps.

So over the course of the series, we’ll fill out what we're calling our Mold Medicine Map, and we'll discover how penicillin kills bacteria – all using organic chemistry! In this episode, we:. Reviewed the reactions that form carboxylic acids.

Recapped nomenclature and explained the properties of carboxylic acids. Reacted carboxylic acids to form salts, and Formed esters and acid chlorides from carboxylic acids. In the next episode, we’ll start looking at how we can use carboxylic acid derivatives to get to other functional groups, and see where some of these reactions fit into our synthesis of penicillin.

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.