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Esters have a wide range of uses, from giving perfumes and colognes their fragrances, to preventing diseases like scurvy. Vitamin C, that scurvy preventing antioxidant, is derived from carboxylic acids, a class of organic compounds we’ve already learned a lot about! In this episode of Crash Course Organic Chemistry, we’ll look at four different carboxylic acid derivatives and their reactivities, react them with nucleophiles, and learn some hydrolysis reaction mechanisms that we can use in our synthesis of penicillin!

Vegas Glitz by Kevin MacLeod

Episode Sources:
Kennedy, J: Common names of carboxylic acids

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!

Esters are found in the  perfumes and colognes we wear,   as well as in the fragrances  of flowers and some fruits. For example, oranges contain octyl  ethanoate, which contributes to their scent. But oranges and other citrus fruits also contain  an ester with important biochemical roles:   the antioxidant vitamin C.

As we talked about in Episode 19, vitamin C  can react with radicals and neutralize them. It’s also used by the body to make collagen,  the main protein found in connective tissues. Not getting enough vitamin C causes scurvy,   a disease that involves jaundice,  bleeding gums, and joint pain.

Vitamin C’s chemical name, ascorbic acid,  comes from the word ‘antiscorbutic’,   which literally means ‘preventing scurvy’. It’s estimated that 2 million sailors died of the  disease between 1500 and 1800 on long voyages. There was some recognition that citrus fruits  helped prevent scurvy, so by 1795,.

British Naval officers were given lemon juice as part  of their rations as a scurvy prevention tactic. But the organic chemistry reasoning eluded them. In the early 1900s, the British Navy  was finding lemons harder to come by.

Limes could be more easily sourced from  British colonies, so they subbed in lime juice under the assumption that the acidity  of citrus fruits was what warded off scurvy. Limes are more acidic than lemons,  but they also contain less vitamin C. So, sometimes, drinking lime juice wasn’t  enough to prevent scurvy in sailors,   and more of them were getting sick again.

It wasn’t until 1932 that vitamin  C, with its ester functional group,   was conclusively linked as the  scurvy-preventing chemical,   and the British Navy realized that their  lemon-to-lime switch was a big mistake! Esters are just one of several compounds  that are derived from carboxylic acids,   and many of them have a fascinating range of uses. In this video, we'll explore some of the others! [Theme Music].

In the last episode, we looked  at carboxylic acid reactions   and saw that using a nucleophile to add groups  to the carbonyl carbon is kind of tricky. Basic nucleophiles pluck off the  proton from the carboxylic acid group,   leaving us with a carboxylate ion. To get around this problem and add to the  carbonyl carbon, we can use the carboxylic acid derivatives we made in the last episode  – specifically acid chlorides and esters.

And we’ll add two more examples of  carboxylic acid derivatives in this episode:   anhydrides and amides. These four carboxylic acid derivatives have different amounts of reactivity at the carbonyl carbon. If it helps, we could think of  them as a barbershop quartet,   four different but interchangeable individuals.

And to understand why, we need to  look closely at their structures. We’ve already learned that  carbonyl compounds have a dipole,   which makes the carbonyl  carbon partially positive. And we know that electronegative  elements exert a strong pull on an electron pair in a covalent bond.

We call this pull an inductive effect. So when there's an electronegative element  like chlorine bonded to the carbonyl carbon,   the inductive effect means that even more electron  density is pulled away from the carbonyl carbon. This makes an acid chloride even more reactive and irresistible to nucleophiles than aldehydes and ketones.

Inductive effects don't completely explain the difference in reactivity of these four carboxylic acid derivatives, though. After all, chlorine, oxygen, and nitrogen atoms  are all pretty electronegative and pull electron density away from the carbonyl carbon so there  must be another reason for the different voices – well, reactivity – in our barber shop quartet. We also need to consider resonance effects!

In carboxylic acid derivatives, the oxygen and  nitrogen atoms have good orbital overlap with the carbonyl carbon's p-orbital, and can donate electron density through resonance. This decreases the partial positive  charge on the carbonyl carbon,   making it less attractive to nucleophiles. Overall, if there's more p-orbital  overlap, we have more resonance effects,   and there's decreased reactivity in our chemical.

So of our four carboxylic acid derivatives,  acid chloride is the most reactive. Chlorine is one of the more electronegative  elements on the periodic table,   so the inductive effects are pretty strong, pull  electron density away from the carbonyl carbon,   and make it more reactive. Plus, chlorine is a row below  carbon on the periodic table,   so they're pretty different in size,  and that leads to poor orbital overlap.

Also, a C-L-plus atom would be unstable,   so any resonance effects are pretty  insignificant for acid chlorides. For anhydrides, esters, and amides, resonance effects make them increasingly  less reactive – in that order. The central oxygen of the anhydride  has resonance with two carbonyl groups   and is sharing electrons in two  directions, so it's next in reactivity.

The ester only shares electrons  with one carbonyl group,   so it has lower reactivity than the anhydride. Finally, nitrogen can handle a positive charge  rather well by comparison to oxygen or chlorine. So that's why amides are the  least reactive of the quartet,   with the weakest inductive effects  and strongest resonance effects.

Now that we understand the reactivity pattern  of our four carboxylic acid derivatives,   it's time to actually play with some reactions! Specifically, we'll just add in a nucleophile   to aim for some nucleophilic  acyl substitution reactions. Even though "substitution"  is right there in the name,   this reaction takes place through  an addition-elimination mechanism.

Remember, we can’t do SN1 and SN2 reactions at  sp2-hybridized carbons like our carbonyl carbon. First, the nucleophile adds on to the carbonyl  carbon, pushing the electrons up onto oxygen and producing a tetrahedral intermediate, like we saw with aldehydes and ketones. But carboxylic acid derivatives, unlike the  aldehydes and ketones we saw in episode 27,   have a built-in leaving group!

See? All four of them have an electronegative  element attached to the carbonyl carbon   that can hop right off the molecule:  the X groups we highlighted here. So, when the electrons push back down,   that X group attached to the carbonyl  carbon is eliminated from the molecule.

Nucleophilic acyl substitution reactions are key steps in the creation of the important plastics, and the nylon found in clothing. They can also be used to form polyesters,  which, as we can see in the name,   are made of a bunch of repeating  ester functional groups. Acyl substitution reactions are also important  in our bodies, as steps in the synthesis and breakdown of important biological  molecules such as proteins and fats.

Many of the fats in the foods we eat  are triglycerides: a combination of three long-chained carboxylic acids and one  glycerol, an alcohol formed from glucose. The carboxylic acid chains link up with  the glycerol molecule through ester groups. So when you eat food containing fats, lipase enzymes in your digestive system catalyze the hydrolysis of those ester groups in triglyceride molecules.

Specifically, this reaction is  called ester hydrolysis and it's a great example of an acyl substitution reaction! It breaks the triglycerides  down into carboxylic acids   which can then be stored as energy  or used for cell repair and growth. Ester hydrolysis of fats is also  a key reaction in soap-making,   such as the ester groups in  animal fats and vegetable oils,   which are both made up of triglycerides.

This ester hydrolysis reaction can also be called a saponification reaction when we're using a strong base to make soap. Base-catalyzed ester hydrolysis starts  with the hydroxide ion attacking and adding on to the carbonyl carbon  to form a tetrahedral intermediate. After this, the electrons push back  down, and the alkoxy group is eliminated,   leaving a carboxylic acid behind.

The alkoxide ion that just got eliminated  is basic, and comes back to pinch a proton from the carboxylic acid, forming an alcohol and leaving a carboxylate ion. So when you wash your hands, for example,   the long, nonpolar hydrocarbon chain  dissolves the oils on your skin. And the charged carboxylate ion allows the soap molecule to interact with water and be washed away.

This base-catalyzed ester hydrolysis is also the reaction that takes place when you use cleaners to try and remove stuck-on grease in your oven! And hydrolysis reactions  aren't exclusive to esters;   all carboxylic acid derivatives  can undergo similar reactions. Anhydrides and acid chlorides are reactive enough that we only need water for hydrolysis to take place.

For esters and amides, though, the  reaction with water alone is too slow. So we need to use an acid or a base as a catalyst  – like we just saw in our saponification reaction. The mechanism for acid-catalyzed hydrolysis of  esters is slightly different from base-catalyzed hydrolysis.

Remember, we don’t want to  form negative charges in acidic solutions! In acid-catalyzed hydrolysis, first, the carbonyl  oxygen grabs a proton from the hydronium ion. Next, a water molecule attacks the carbonyl carbon  to give us our familiar tetrahedral intermediate.

In base-catalyzed hydrolysis,   this is when the electrons pushed back  down and we kicked out an alkoxide ion. But negatively charged alkoxide ions  aren’t stable in acidic solutions,   so that isn’t possible here  in acid-catalyzed hydrolysis. Instead, our mechanism changes in  acid to avoid negative charges.

So the alkoxy group gets protonated  first, and then it leaves as an alcohol. After this, the water  deprotonates the carbonyl oxygen,   and we're left with a carboxylic  acid as our other product. And we're done!

Hydrolysis reactions pop up at a couple of  points during our synthesis of penicillin. Let’s fill these in on our Mold Medicine Map  that will document the steps in penicillin V synthesis, as it was first done by the  organic chemist Dr. John C.

Sheehan. As we learn the reactions throughout the  rest of the series, we'll add to the map! In this early step of penicillin synthesis, we use acid-catalyzed ester hydrolysis to convert an ester group into a carboxylic acid,  which we've already seen the mechanism for!

You’ll notice that there’s another  functional group transformation here, too:   the amide group is hydrolyzed to form an amine. Let’s take a closer look at  the amide hydrolysis mechanism,   using what we learned in the ester hydrolysis  examples from earlier in this episode. Remember that esters are more reactive than  amides as functional groups on carboxylic acid derivatives, so the ester hydrolysis reaction  will probably happen before the amide hydrolysis.

Base-catalyzed hydrolysis is possible with amides,   but this requires a strong base and lots of heating. So acid-catalyzed hydrolysis is more common. The first few steps of an acid-catalyzed amide  hydrolysis are similar to we saw with the ester.

First, the carbonyl oxygen grabs  a proton from the hydronium ion. This leaves a water molecule behind,  which attacks the carbonyl carbon,   and once again gives us a  tetrahedral intermediate. In the next steps, a proton is removed from the positively charged oxygen and transferred to the nitrogen.

This makes for an excellent leaving group,  and it’s booted out to form an amine. Later in the penicillin synthesis,   we see acid-catalyzed hydrolysis again,  only with an ester instead of an amide. About midway through the synthesis, an ester containing a bulky tert-butyl is put on the molecule to act as a protecting group,   which stops the carboxylic acid group from reacting when we want other parts of the structure to react instead.

This protecting group needs to be removed later in the synthesis so we can form the penicillin structure’s four-membered ring. And that's where the acid-catalyzed  ester hydrolysis comes in! This reaction isn’t done in water,  so it’s a different mechanism,   but the end result is the same — a carboxylic acid.

We’ll learn a bunch about protecting  groups in just a couple of episodes,   so consider this a sneak preview. Our Mold Medicine Map features a few other  steps involving carboxylic acid derivatives,   so we’ll continue playing with these compounds  and their reactions in the next episode. But in this episode, we:.

Identified four carboxylic acid derivatives  and looked at their different reactivities,. Reacted nucleophiles with  carboxylic acid derivatives, and. Learned some hydrolysis reaction mechanisms to  make carboxylic acids and carboxylate salts.

In the next episode, we’ll look at how we can interconvert between the carboxylic acid derivatives we’ve met in this episode,   and learn about some other important reactions. 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.