Carboxylic Acid Derivatives & Hydrolysis Reactions: Crash Course Organic Chemistry #31

Summary

This Crash Course Organic Chemistry segment explores the diverse roles of esters, including their presence in scents and as vitamin C, which prevents scurvy. It delves into carboxylic acid derivatives' reactivity, influenced by inductive and resonance effects, and their applications in acyl substitution reactions. The video also covers ester hydrolysis in digestion and soap-making, and its significance in penicillin synthesis, offering a comprehensive look at these compounds' importance in chemistry and biology.

Takeaways

• 🍊 Esters are compounds found in perfumes, colognes, and the fragrances of flowers and fruits, including oranges which contain octyl ethanoate.
• 🍋 Oranges and other citrus fruits contain vitamin C, an ester with antioxidant properties and crucial for collagen production.
• 🚑 A deficiency in vitamin C can lead to scurvy, characterized by jaundice, bleeding gums, and joint pain.
• 🌊 Historically, British sailors were given lemon juice to prevent scurvy, but later switched to lime juice due to availability, which was less effective due to lower vitamin C content.
• 🧪 It wasn't until 1932 that vitamin C was identified as the key scurvy-preventing compound, correcting the British Navy's mistake.
• 🔬 Esters are one of several compounds derived from carboxylic acids, each with unique reactivities and uses.
• 🌐 The reactivity of carboxylic acid derivatives is influenced by both inductive and resonance effects, with acid chlorides being the most reactive.
• 🧩 Nucleophilic acyl substitution reactions are key in the synthesis of plastics, nylon, and polyesters, and are also vital in biological processes.
• 🍲 Ester hydrolysis is a critical reaction in the digestion of dietary fats and in soap-making, involving the breakdown of triglycerides into carboxylic acids and glycerol.
• 🧼 The saponification reaction, a type of ester hydrolysis, is used to make soap and involves the use of a strong base to catalyze the reaction.
• 💊 Hydrolysis reactions are also integral to the synthesis of penicillin, including the conversion of esters to carboxylic acids and amides to amines.

Q & A

What is the role of esters in perfumes and colognes?

Esters contribute to the fragrances found in perfumes and colognes, as well as in the natural scents of flowers and some fruits like oranges.

Which ester found in oranges is responsible for their scent?

Octyl ethanoate is the ester found in oranges that contributes to their characteristic scent.

What is the biochemical role of the ester vitamin C?

Vitamin C, also known as ascorbic acid, acts as an antioxidant by neutralizing radicals and is used by the body to synthesize collagen, a main protein in connective tissues.

What historical disease was caused by a deficiency of vitamin C?

Scurvy is the disease caused by a lack of vitamin C, characterized by symptoms such as jaundice, bleeding gums, and joint pain.

How did the British Navy initially prevent scurvy among sailors?

The British Navy initially prevented scurvy by providing lemon juice to officers as part of their rations, recognizing that citrus fruits helped prevent the disease.

Why did the British Navy switch from lemon to lime juice for scurvy prevention?

The British Navy switched to lime juice because lemons became harder to source, and limes were more readily available from British colonies. However, this switch was a mistake because limes contain less vitamin C than lemons.

What is the significance of the year 1932 in relation to vitamin C?

In 1932, vitamin C was conclusively linked to the prevention of scurvy, leading the British Navy to realize their mistake in switching from lemon to lime juice.

How do carboxylic acid derivatives like acid chlorides and esters help in reactions with nucleophiles?

Carboxylic acid derivatives such as acid chlorides and esters allow for the addition of groups to the carbonyl carbon without the nucleophile simply removing a proton from the carboxylic acid group.

What is the role of inductive and resonance effects on the reactivity of carboxylic acid derivatives?

Inductive effects increase the reactivity of carboxylic acid derivatives by pulling electron density away from the carbonyl carbon due to the presence of electronegative elements. Resonance effects decrease reactivity by donating electron density through orbital overlap, reducing the partial positive charge on the carbonyl carbon.

Why are amides the least reactive among the carboxylic acid derivatives discussed?

Amides are the least reactive because nitrogen can handle a positive charge well, leading to weaker inductive effects and stronger resonance effects compared to other derivatives.

What is the significance of nucleophilic acyl substitution reactions in the creation of plastics and nylon?

Nucleophilic acyl substitution reactions are key steps in the synthesis of important plastics and nylon, as they involve the addition of nucleophiles to carboxylic acid derivatives.

How does ester hydrolysis play a role in the digestion of fats?

Ester hydrolysis is catalyzed by lipase enzymes in the digestive system, breaking down ester groups in triglyceride molecules into carboxylic acids, which can be used for energy storage or cell repair and growth.

What is the difference between base-catalyzed and acid-catalyzed ester hydrolysis?

Base-catalyzed ester hydrolysis involves a hydroxide ion attacking the carbonyl carbon to form a tetrahedral intermediate, while acid-catalyzed hydrolysis starts with the carbonyl oxygen grabbing a proton from a hydronium ion before water attacks the carbonyl carbon.

How are hydrolysis reactions utilized in the synthesis of penicillin?

Hydrolysis reactions are used in the synthesis of penicillin to convert ester groups into carboxylic acids and amides into amines, which are crucial steps in the formation of the penicillin structure.

Outlines

00:00

🍊 Esters in Nature and Their Health Impact

This section introduces esters as organic compounds found in perfumes, colognes, and the natural fragrances of flowers and fruits, like oranges which contain octyl ethanoate. It highlights the ester ascorbic acid (vitamin C), crucial for human health, as it acts as an antioxidant and aids in collagen production. A deficiency leads to scurvy, historically a problem for sailors on long voyages. The narrative recounts how British naval officers were given lemon juice to prevent scurvy, but the switch to lime juice due to availability issues was less effective. This historical context underscores the importance of understanding the chemistry behind the health benefits of these compounds. The paragraph also delves into the chemistry of carboxylic acid derivatives, explaining how their reactivity varies due to inductive and resonance effects, with acid chlorides being the most reactive and amides the least.

05:00

🧪 Nucleophilic Acyl Substitution Reactions

This part of the script discusses the reactivity of carboxylic acid derivatives, focusing on nucleophilic acyl substitution reactions. It explains that these reactions occur through an addition-elimination mechanism, as opposed to SN1 and SN2 reactions, due to the sp2-hybridized carbonyl carbon. The script describes how these reactions are integral to the synthesis of plastics, nylon, and polyesters, and are also vital in biological processes like protein and fat metabolism. It provides an example of ester hydrolysis in the digestion of triglycerides and in soap-making, highlighting the saponification reaction. The section also touches on acid-catalyzed hydrolysis, contrasting it with base-catalyzed hydrolysis and explaining the mechanism to avoid negative charges in acidic conditions.

10:03

🧪 Hydrolysis Reactions in Organic Synthesis

The final section covered in the script explores hydrolysis reactions in the context of organic synthesis, specifically in the production of penicillin. It details how acid-catalyzed ester hydrolysis is used to convert ester groups into carboxylic acids and how amides are hydrolyzed to form amines. The script explains the mechanism of acid-catalyzed amide hydrolysis and how protecting groups, like the tert-butyl group, are used to prevent unwanted reactions during synthesis. It also previews the concept of protecting groups and hints at future episodes that will delve deeper into these topics. The section wraps up by summarizing the key points: identifying carboxylic acid derivatives, their reactions with nucleophiles, and learning hydrolysis mechanisms to produce carboxylic acids and carboxylate salts.

Keywords

💡Esters

Esters are organic compounds that are formed by the reaction of an acid and an alcohol. They are widely used in the production of perfumes, colognes, and are naturally found in fruits like oranges. In the script, octyl ethanoate is mentioned as an ester contributing to the scent of oranges. Vitamin C, or ascorbic acid, is also an ester with significant biochemical roles, such as acting as an antioxidant and aiding in collagen production.

💡Vitamin C

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin that is essential for the human body. It is highlighted in the script for its antioxidant properties, where it can neutralize harmful radicals, and for its role in collagen synthesis. A deficiency in vitamin C can lead to scurvy, which was historically a significant problem among sailors on long voyages.

💡Scurvy

Scurvy is a disease caused by a deficiency of vitamin C, characterized by symptoms like jaundice, bleeding gums, and joint pain. The term is used in the script to illustrate the historical importance of vitamin C and how its discovery and understanding were crucial for sailors to prevent the disease, particularly through the consumption of citrus fruits.

💡Carboxylic Acid Derivatives

Carboxylic acid derivatives are compounds that are derived from carboxylic acids through various chemical reactions. The script discusses four main types: acid chlorides, esters, anhydrides, and amides. These derivatives are important in organic chemistry due to their different reactivities and applications in the synthesis of plastics, pharmaceuticals, and other materials.

💡Inductive Effect

The inductive effect is a phenomenon in chemistry where the electron-withdrawing ability of a substituent atom or group affects the reactivity of a molecule. In the script, the inductive effect is discussed in the context of carboxylic acid derivatives, explaining how electronegative elements like chlorine can increase the reactivity of acid chlorides by pulling electron density away from the carbonyl carbon.

💡Resonance Effects

Resonance effects occur when a molecule can be represented by two or more Lewis structures that contribute to the overall stability of the molecule. In the script, resonance is used to explain the decreased reactivity of carboxylic acid derivatives like esters and amides, where electron density is delocalized through resonance, reducing the partial positive charge on the carbonyl carbon.

💡Nucleophiles

Nucleophiles are molecules or ions that donate an electron pair to an electron-deficient species in a chemical reaction. The script discusses how nucleophiles interact with carboxylic acid derivatives, particularly in nucleophilic acyl substitution reactions, which are crucial for the synthesis of plastics, polyesters, and biological molecules like proteins and fats.

💡Acyl Substitution Reactions

Acyl substitution reactions are a type of chemical reaction where a nucleophile replaces a leaving group in an acyl compound. The script explains that these reactions occur through an addition-elimination mechanism and are key in the synthesis of materials like nylon and polyesters, as well as in biological processes such as the digestion of fats.

💡Ester Hydrolysis

Ester hydrolysis is a reaction where an ester reacts with water to produce a carboxylic acid and an alcohol. This process is highlighted in the script as a key step in the digestion of dietary fats and in soap-making through a process called saponification. The reaction mechanism involves the nucleophilic attack of water on the carbonyl carbon of the ester.

💡Protecting Groups

Protecting groups are chemical groups used in organic synthesis to temporarily mask a functional group from reacting while other reactions occur. The script mentions a tert-butyl group as a protecting group in the synthesis of penicillin, preventing the carboxylic acid group from reacting until it is deprotected through ester hydrolysis.

💡Penicillin Synthesis

The synthesis of penicillin is a complex organic chemical process that involves multiple steps, including the use of carboxylic acid derivatives and their reactions. The script uses the synthesis of penicillin V as an example to illustrate the application of ester hydrolysis and amide hydrolysis in the creation of this important antibiotic.

Highlights

Esters are found in perfumes, colognes, and natural fragrances like oranges and flowers.

Oranges contain octyl ethanoate, contributing to their scent.

Vitamin C, an ester, has antioxidant properties and is essential for collagen production.

Vitamin C deficiency leads to scurvy, characterized by jaundice, bleeding gums, and joint pain.

Vitamin C's chemical name, ascorbic acid, means 'preventing scurvy'.

Between 1500 and 1800, 2 million sailors died of scurvy on long voyages.

British Naval officers were given lemon juice as a scurvy prevention tactic by 1795.

In the early 1900s, the British Navy switched to lime juice due to lemon shortages.

Limes contain less vitamin C than lemons, leading to scurvy in sailors despite lime juice.

Vitamin C was conclusively linked to scurvy prevention in 1932.

Esters are one of several compounds derived from carboxylic acids with various uses.

Carboxylic acid derivatives include acid chlorides, esters, anhydrides, and amides.

The reactivity of carboxylic acid derivatives varies due to inductive and resonance effects.

Acid chlorides are the most reactive due to strong inductive effects and poor orbital overlap.

Resonance effects decrease reactivity in anhydrides, esters, and amides in that order.

Nucleophilic acyl substitution reactions are key in creating plastics and nylon.

Ester hydrolysis is a key reaction in the digestion of fats and in soap-making.

Base-catalyzed ester hydrolysis, or saponification, is used to make soap from animal fats and vegetable oils.

Acid-catalyzed hydrolysis of esters involves a different mechanism than base-catalyzed hydrolysis.

Hydrolysis reactions are part of penicillin synthesis, including ester and amide hydrolysis.

Protecting groups, like bulky tert-butyl groups, are used in penicillin synthesis to prevent unwanted reactions.

Acid-catalyzed ester hydrolysis is used to remove protecting groups in penicillin synthesis.

Transcripts

You can review content from Crash Course Organic Chemistry with the Crash Course App,

available now for Android and iOS devices.

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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