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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.
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