Carboxylic Acid Derivatives - Interconversion & Organometallics: Crash Course Organic Chemistry #32

Summary

This Crash Course Organic Chemistry episode explores carboxylic acid derivatives, focusing on their interconversion and reactions. Deboki Chakravarti explains how these derivatives, such as acid chlorides, anhydrides, esters, and amides, can be transformed into each other, with a key rule that more reactive forms can only be converted to less reactive ones. The episode also delves into the synthesis of acetaminophen, a unique painkiller, and touches on the creation of penicillin V and the reduction of these derivatives using metal hydrides, illustrating their importance in organic chemistry.

Takeaways

• 💊 Carboxylic acid derivatives are important in the synthesis of common painkillers like acetaminophen (Tylenol).
• 🧬 Painkillers work in different ways: NSAIDs like aspirin and ibuprofen work at the site of pain, while opioids like morphine block pain signals in the nervous system.
• 🔍 Acetaminophen's exact mechanism of action is not fully understood, but it's known to be different from NSAIDs and opioids.
• 🔄 Carboxylic acid derivatives can be interconverted, but the rule is you can only easily convert a more reactive derivative to a less reactive one.
• 🧪 Acid chlorides are the most reactive and can be converted to any of the other three less reactive derivatives: anhydrides, esters, and amides.
• 🌿 Aspirin contains an ester and can be synthesized from acetic anhydride and salicylic acid, originally extracted from willow tree bark.
• 🧬 Amides are the least reactive carboxylic acid derivatives but are found in many drugs, proteins, Kevlar, and insect repellents like DEET.
• 💊 Penicillin V synthesis involves the reaction of an amino acid with an acid chloride to form a key part of its structure.
• 🧪 Esters can be transformed into tertiary alcohols using Grignard reagents, and acid chlorides can be reduced to ketones using Gilman reagents.
• 🧪 Lithium aluminum hydride can reduce carboxylic acid derivatives to alcohols, aldehydes, or amines, depending on the conditions and the derivative.

Q & A

What is the main focus of this Crash Course Organic Chemistry episode?

The main focus of this episode is to dive deeper into carboxylic acid derivatives, their interconversions, and their applications in the synthesis of medicines like acetaminophen (Tylenol) and penicillin.

How does acetaminophen differ from other painkillers?

Acetaminophen, unlike other painkillers, does not fall into the categories of non-steroidal anti-inflammatory drugs or opioids. Its exact mechanism of action is still not completely understood, although some theories exist.

What are the four carboxylic acid derivatives mentioned in the script?

The four carboxylic acid derivatives mentioned are acid chlorides, anhydrides, esters, and amides.

What is the key rule when interconverting carboxylic acid derivatives?

The key rule is that one can only easily convert one derivative to a less-reactive derivative.

How is acetic anhydride produced according to the script?

Acetic anhydride is produced by reacting an acid chloride with a carboxylic acid salt, or by reacting a carboxylic acid with pyridine, which deprotonates the acid and forms a carboxylate salt.

What is a symmetrical anhydride and how can you identify it?

A symmetrical anhydride is one where the groups attached to each of the carbonyl carbons are the same. It can be identified if the name has only two parts.

How can an anhydride be converted into an ester?

An anhydride can be converted into an ester by reacting it with an alcohol, which results in the anhydride being cut down the middle and one carbonyl group forming the ester.

What is the role of amides in carboxylic acid derivatives?

Amides are the least reactive of the carboxylic acid derivatives but are important in many applications, including being present in proteins, Kevlar, DEET, and a quarter of all marketed drugs.

How is penicillin V synthesized starting from valine?

Penicillin V synthesis starts with valine, an essential amino acid, where its primary amine group reacts with 2-chloroacetyl chloride to form part of the 4-membered beta-lactam ring found in penicillin.

What is the role of organometallic reagents in the reactions of carboxylic acid derivatives?

Organometallic reagents, such as Grignard reagents, can react with carboxylic acid derivatives like esters to form tertiary alcohols, and with acid chlorides to potentially form ketones.

How can carboxylic acid derivatives be reduced using metal hydrides?

Carboxylic acid derivatives can be reduced using metal hydrides like lithium aluminum hydride, which can reduce esters to aldehydes or alcohols, and amides to amines.

Outlines

00:00

🧪 Carboxylic Acid Derivatives and Painkillers

The paragraph introduces the topic of carboxylic acid derivatives, focusing on their role in creating acetaminophen, a common painkiller. It contrasts acetaminophen with other painkillers like aspirin and ibuprofen, which are anti-inflammatory, and opioids like morphine, which block pain signals. The paragraph also discusses the different methods of synthesizing acetaminophen and introduces the concept of interconversion between carboxylic acid derivatives, explaining the rule that one can only easily convert a more reactive derivative to a less reactive one. Examples of such conversions are provided, including the transformation of acid chlorides to anhydrides and esters, and the synthesis of acetaminophen from p-aminophenol and acetic anhydride.

05:02

🧬 Synthesis of Amides and Penicillin V

This section delves into the synthesis of amides, starting with the conversion of acid chlorides to amides using ammonia or amines. It explains the need for two equivalents of these reagents and the formation of salts with hydrochloric acid byproducts. The process is further detailed for anhydrides and esters, with the latter requiring only one equivalent of ammonia or amine due to the formation of an alcohol. The paragraph then ties amides to the synthesis of penicillin V, starting from valine and reacting with 2-chloroacetyl chloride, forming part of the beta-lactam ring. It also mentions the use of carboxylic acid derivatives with organometallic reagents, such as Grignard reagents, to form tertiary alcohols and ketones, and the reduction of esters to aldehydes using DIBAL-H.

10:07

🔬 Reduction Reactions and Opioid Synthesis

The final paragraph covers the reduction reactions of carboxylic acid derivatives using metal hydrides, like lithium aluminum hydride, which can reduce esters to aldehydes and amides to amines. It describes the mechanism of these reductions, involving nucleophilic attack by the hydride ion and the formation of tetrahedral intermediates. The paragraph also highlights the use of DIBAL-H to stop the reduction at the aldehyde stage and the importance of safely handling reactive reducing agents. It concludes by connecting the reduction of amides back to the synthesis of morphine, an opioid painkiller, emphasizing the practical applications of the discussed chemistry.

Keywords

💡Carboxylic Acid Derivatives

Carboxylic acid derivatives are compounds that are formed by the reaction of a carboxylic acid with another molecule. They are key in organic chemistry and include acid chlorides, anhydrides, esters, and amides. In the video, these derivatives are discussed extensively as they are used to synthesize various pharmaceuticals, including acetaminophen and penicillin V. The script mentions how these derivatives can be interconverted and used in different reactions to produce useful compounds.

💡Acetaminophen

Acetaminophen, also known as paracetamol or tylenol, is a common painkiller mentioned in the script. It is unique among painkillers because its exact mechanism of action is not fully understood, unlike other categories like NSAIDs or opioids. The script explains that acetaminophen can be synthesized from p-aminophenol and acetic anhydride, which are carboxylic acid derivatives.

💡Acid Chlorides

Acid chlorides are reactive carboxylic acid derivatives that can be converted into other less reactive derivatives. They are the most reactive of the carboxylic acid derivatives and are used in the synthesis of various compounds. The video script describes how acid chlorides can be converted into anhydrides, esters, and amides, highlighting their versatility in organic synthesis.

💡Anhydrides

Anhydrides are carboxylic acid derivatives formed by the removal of water from two molecules of a carboxylic acid. They are less reactive than acid chlorides but more reactive than esters and amides. The script discusses how anhydrides can be converted into esters and amides, and it also mentions acetic anhydride as a precursor in the synthesis of acetaminophen and aspirin.

💡Esters

Esters are formed from the reaction of an acid and an alcohol and are less reactive than anhydrides. They are used in the synthesis of aspirin from salicylic acid and acetic anhydride, as mentioned in the script. Esters can also be reduced to form alcohols, showcasing their importance in organic chemistry.

💡Amides

Amides are carboxylic acid derivatives formed by the reaction of an acid with an amine. They are the least reactive of the carboxylic acid derivatives but are found in many biologically important molecules, such as proteins and drugs. The script explains how amides can be synthesized from acid chlorides, anhydrides, and esters, and it also mentions their role in the synthesis of penicillin V.

💡Nucleophiles

Nucleophiles are species that donate an electron pair and are attracted to positively charged centers or electrophiles. In organic chemistry, nucleophiles often react with carboxylic acid derivatives. The script discusses how these derivatives can react with nucleophiles or undergo hydrolysis, which is a reaction with water acting as a nucleophile.

💡Organometallic Reagents

Organometallic reagents are compounds containing a bond between carbon and a metal. They are used as strong nucleophiles in organic synthesis. The script describes how organometallic reagents like Grignard reagents can react with carboxylic acid derivatives, such as esters, to form alcohols and ketones.

💡Reduction

Reduction is a chemical reaction in which a molecule gains electrons, often involving the addition of hydrogen or the removal of oxygen. The script explains how carboxylic acid derivatives can be reduced using metal hydrides like lithium aluminum hydride, which can convert esters to alcohols and amides to amines.

💡Penicillin V

Penicillin V is a type of antibiotic derived from the Penicillium mold. It contains amide groups and is synthesized from valine, an essential amino acid. The script details the synthesis of penicillin V, highlighting the role of carboxylic acid derivatives and their reactions in forming the final antibiotic structure.

💡Morphine

Morphine is an opioid painkiller derived from the opium poppy. The script mentions that the reduction of an amide group, a key step in the synthesis of morphine, involves the use of lithium aluminum hydride to convert a tertiary amide group to a tertiary amine, which is a characteristic group in all opioid painkillers.

Highlights

Crash Course Organic Chemistry is available on the Crash Course App for Android and iOS.

Deboki Chakravarti introduces the topic of carboxylic acid derivatives.

Carboxylic acid derivatives can be used to make acetaminophen, a common painkiller.

Acetaminophen's mechanism of action is not fully understood despite its effectiveness.

There are multiple ways to synthesize acetaminophen, including from p-aminophenol and acetic anhydride.

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

Derivatives can be interconverted, but only to less reactive forms.

Acid chlorides can be converted to anhydrides using a carboxylic acid salt.

Acetic anhydride is a symmetrical anhydride and a precursor to Tylenol.

Anhydrides can be converted to esters by reacting with an alcohol.

Acid chlorides can be converted to esters using an alcohol and a mild base.

Amides are the least reactive carboxylic acid derivatives but are found in many drugs and proteins.

Acid chlorides can be converted to amides using ammonia or amines.

Anhydrides can also be converted to amides with ammonia or amines.

Esters can be converted to amides using one equivalent of ammonia or amine.

Valine, an essential amino acid, is used in the synthesis of penicillin V.

Carboxylic acid derivatives can react with organometallic reagents like Grignard reagents.

Esters react with Grignard reagents to form tertiary alcohols.

Acid chlorides can be reduced with organocuprate reagents to form ketones.

Carboxylic acid derivatives can be reduced using metal hydrides like lithium aluminum hydride.

Esters can be reduced to aldehydes using DIBAL-H.

Amides can be reduced to amines using lithium aluminum hydride.

Reduction of amides is a key step in the synthesis of morphine.

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!

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 antiinflammatory 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.

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