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We’ve already learned the basics of carbonyl chemistry and talked about how we can synthesize aldehydes and ketones, but there’s still so much more to learn, like the role carbonyl groups play in reactions involving sedatives! In this episode of Crash Course Organic Chemistry we’re diving deeper into aldehydes and ketones by focusing on addition reactions of oxygen and nitrogen based nucleophiles. We’ll cover hydrates, acetals and hemiacetals, imines and enamines, and more!

Episode Sources:
io9. 2020. This Is The Drug In The Rolling Stones' Song "Mother's Little Helper". [online] Available at: https://io9.gizmodo.com/this-is-the-drug-in-the-rolling-stones-song-mothers-li-1693032181
Bionity.com. 2020. Mickey_Finn_(Drugs). [online] Available at: https://www.bionity.com/en/encyclopedia/Mickey_Finn_%28drugs%29.html#The_Chicago_bartender_Michael_.22Mickey.22_Finn
Chm.bris.ac.uk. 2020. Ninhydrin - Molecule Of The Month - April 2018. [online] Available at: http://www.chm.bris.ac.uk/motm/ninhydrin/ninhydrinh.htm
Ewan, H.S., Iyer, K., Hyun, S.H., Wleklinski, M., Cooks, R.G. and Thompson, D.H., 2017. Multistep flow synthesis of diazepam guided by droplet-accelerated reaction screening with mechanistic insights from rapid mass spectrometry analysis. Organic Process Research & Development, 21(10), pp.1566-1570.

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!

Back in episode 27, we talked a lot about the synthesis of aldehydes and ketones. And now that we know the basics, we can build up to some more familiar chemical reactions involving the carbonyl group, a carbon attached to an oxygen with a double bond. Stick with me for a second, I'm a huge fan of reality TV.

I can't stop watching everything in the Bravo Cinematic Universe. And a common character trope – though it's definitely unhealthy and we should probably question why it's become so normalized – is the overstressed mom who takes anti-anxiety pills to make it through the day. This stereotype has been around since the 1960s, and was even immortalized in the Rolling Stones song "Mother's Little Helper." It's complicated, because sedatives like Xanax or Valium can be prescribed as anti-anxiety medication and really help people!

But they have also been abused. Because our focus here is organic chemistry, in this episode we'll learn what these sedatives all have in common: carbonyl chemistry. [Theme Music]. Thanks to the polar C=O bond in a carbonyl group, the carbonyl carbon has a partially positive charge.

In episode 27, we talked about cyanide, acetylide anions, and the phosphonium ylides used in the Wittig reaction attacking this partially positive carbon. These reactions extend the carbon chain, allowing us to make bigger, more complicated molecules. And other nucleophiles can also attack the carbonyl group!

In this episode, we’ll focus on addition reactions of oxygen- and nitrogen-based nucleophiles. A simple oxygen-based nucleophile that we're already quite familiar with is water. If you mix water with an aldehyde or ketone, an equilibrium forms with a hydrate form, called geminal-diols or gem-diols.

The word geminal is similar to geminus, one of several Latin words describing twins. And in chemistry, "geminal" is used when we’re talking about a molecule with two or more of the same functional group attached to a single atom. Usually, this equilibrium favors the aldehyde or ketone because of inductive effects.

Groups like methyls or ethyls are electron releasing, meaning they push electrons towards the partially positive carbon in a carbonyl and stabilize it. There are examples that break this pattern, though, like the smallest aldehyde: formaldehyde. Mixing water with formaldehyde produces a solution called formalin.

Formalin helps preserve tissues from decay, so it's what scientists use to preserve tissue specimens in jars. And not just scientists, artists too –. Damien Hirst exhibited a whole preserved tiger shark.

Thinking about inductive effects, the hydrogen atoms on formaldehyde don’t do much to stabilize the partial positive charge on the carbon. So the equilibrium in a formalin solution very much favors the gem-diol – not the aldehyde. We can also make stable gem-diols by substituting aldehydes with strong electron-withdrawing groups, like chlorine, which destabilize the partial positive charge on the carbonyl carbon.

For example, if we mix 2,2,2-trichloroacetaldehyde with water it forms chloral hydrate, which was given as a sedative in asylums and much abused in the late 19th century. Chloral hydrate in ethanol is colloquially known as “knockout drops” or a Mickey Finn, which is probably named after a Chicago bartender who gained infamy after using this mixture to incapacitate and steal from some of his customers. Big yikes.

Now, we can also react carbonyl compounds with other oxygen-based nucleophiles, like alcohol groups. When a single alcohol group adds to an aldehyde, we get a hemiacetal. The name comes from the Greek word hèmi, meaning half, because only one alcohol is added.

There are also full-blown acetals that we'll talk about in a bit, which have two alcohol groups added! Hemiacetals are generally less stable than their aldehyde equivalents, so the equilibrium favors the aldehyde – as it does with many gem-diols. Sugars (and other molecules that can form intramolecular and cyclic hemiacetals) can be exceptions.

In aqueous solution, glucose rapidly interconverts between its straight-chain and cyclic forms when one of its alcohol groups attacks its carbonyl carbon. Since the carbonyl group in glucose has a trigonal planar geometry and our intramolecular hydroxy nucleophile can attack from either side, our hemiacetal products are two diastereomers. But we can get even more specific in what we call them!

The sugar world actually has lots of special vocabulary: the hemiacetal carbon of a sugar is called the anomeric carbon. So these two products are more precisely called anomers, one labeled alpha and one labeled beta. In the beta anomer, these groups end up on the same side, and in the alpha anomer, these groups are opposite.

The beta anomer of glucose is actually favored in water because (similar to cyclohexane) it can adopt a comfy, stable chair conformation. And all the groups are equatorial, which also helps reduce steric hindrance and increase stability. That covers the basics of hemiacetals, so now let's take off that "hemi" prefix and make acetals, which form when two alcohol groups add to an aldehyde or a ketone.

These reactions are acid-catalyzed, so the three players are a carbonyl group, an alcohol, and acid. Looking at the summary reaction, we can see that we need to add two molecules of methanol to the carbonyl carbon to form the product. So let’s puzzle through the mechanism.

If we added methanol as a first step, that would give us a negative charge – which we can’t have in an acid! Okay, so we've gotta try something else to start. In acidic conditions, we have protons.

And there’s a lone pair on the carbonyl oxygen. So... what if that lone pair grabbed a proton from an oxonium ion? We'd have a positive charge, which is totally fine in our acid!

Even though this works as a first step, the oxygen isn’t happy about this whole positive-charge situation. It draws a pair of electrons in the carbon-oxygen double bond towards itself, making the carbonyl carbon very electropositive and prone to nucleophilic attack. Looking at our product, we want to add methoxy groups to that carbon.

So that means the nucleophile we choose for this attack is our alcohol. Specifically, a lone pair on the oxygen of one of the alcohol molecules attacks the carbonyl carbon, and adds a methanol. We've still got a positive charge on the molecule, though, so this isn't stable enough to be an end product.

We've got to make our way to a neutral molecule somehow. Remember we’ve got plenty of alcohol molecules floating around, with two lone pairs on their oxygen atoms. So one of those alcohols can grab the spare proton on our molecule, leaving us with an -OH and an -OR group attached to the what-was-a-carbonyl carbon.

Now we have a hemiacetal, so we're getting closer! But to have a full-blown acetal, we need another methoxy group instead of that OH. In our acidic conditions, we can get rid of the OH by making it a good leaving group.

That OH grabs a proton from a protonated molecule of methanol. We might be tempted to have another molecule of methanol attack and kick off water at this point… but that would be like SN2 at a tertiary carbon, which doesn't work because, remember, there's not enough room for the backside attack! Instead, we get a little help from the adjacent oxygen.

A lone pair of electrons on the oxygen of the newly-attached alcohol group help push out water, forming an oxonium ion and a molecule that's… not that different from where we started! Except now, instead of a protonated carbonyl, we have a carbonyl attached to a methyl group on oxygen. The similarity is important to notice because we can basically do the same set of moves again: a nucleophilic attack from another alcohol molecule, followed by deprotonation, and we get our acetal with two methoxy groups.

We're done! That was a lot, so let’s review all the steps of our reaction mechanism with the arrow pushing. In these acidic conditions, this process is reversible.

Heat an acetal with water and acid, and, boom! Back to the ketone or aldehyde. But if acid isn’t present, acetals are really stable once they’re formed.

In fact, they won’t even react with really strong nucleophiles like carbanions. Acetal formation is an important strategy for controlling the reactivity of aldehydes and ketones in multistep reactions, so we’ll come back to this when we talk about protecting groups in a later episode. For now, we'll move onto another similar reaction, involving the formations of imines and enamines.

Imines are molecules with carbon-nitrogen double bonds, and enamines contain a carbon-carbon double bond next to an amine… an alkENE plus an AMINE! Imines come from a carbonyl and a primary amine, while enamines come from secondary amines. One way to remember the difference is to notice that the words “imine” and “amine” are the same except for one letter – so imines come from primary amines. “Enamine” on the other hand, has two extra letters, so enamines come from secondary amines.

The mechanism for imine formation is similar to acetal formation, with three main players: a carbonyl group, a primary amine, and acidic conditions. Once again, there's a lone pair on the carbonyl oxygen that can grab a proton. Then the nucleophile – which is the nitrogen in the amine this time – can attack the carbon atom of the protonated carbonyl group.

The pi electrons in the carbon-oxygen double bond neutralize the oxonium ion, and our intermediate molecule has an amine and OH on the what-was-a-carbonyl carbon. As in acetal formation, oxygen gets protonated, the nitrogen lone pair forms a carbon-nitrogen double bond, and water is eliminated. That leaves us with an iminium ion, which is any molecule with a positive charge on the double bonded nitrogen.

After a deprotonation, we get an imine. However, if we're making an enamine and start with a carbonyl group, a secondary amine, and acidic conditions, we can’t do this final deprotonation step. The nitrogen has two R groups instead of a hydrogen we can just kick out.

So, instead, the final step of the mechanism is deprotonating the carbon adjacent to our iminium ion, giving us an enamine. This is a great moment to mention a compound called ninhydrin, which is used in chromatography to identify amino acids and forensics to view fingerprints. Specifically, ninhydrin detects the amines present in the amino acids and proteins left behind by our fingerprints.

When it reacts with amino acids, a deep blue-purple color appears, called Ruhemann’s purple. This is actually an imine-forming reaction that occurs on the keto form of ninhydrin! And the mechanism is fairly straightforward.

That central carbonyl carbon in the five-membered ring – smooshed between all those carbonyl groups – has a big partially positive charge. So it's really attractive to nucleophiles. As a result, when an amine turns up, say from the oily residue left by a finger, the lone pair on the nitrogen attacks the central carbon.

Then, the ninhydrin is dehydrated, and we form an imine! The next few steps of this mechanism are beyond the scope of this episode, but basically, another molecule of ninhydrin reacts, and the two molecules link up through the nitrogen atom. This compound is responsible for that pretty purple color – and successful fingerprint sleuthing!

To continue linking our carbonyl chemistry to real-world applications, we can also look at the anti-anxiety medicine – that stereotype of dramatic TV. We talked about Valium to start, which is a brand name for diazepam. The chemist Leo Sternbach, and his gifted technician, Beryl Kappell, discovered the first of this family of compounds by accident in the mid 1950s – called chlordiazepoxide.

Kappell had been screening potential muscle relaxants for seven years when she found that this compound had anxiety-reducing effects. A few years later, the discovery of diazepam followed. These drugs quickly became popular because they reduce anxiety and tension without the “knock-out” effect of something like chloral hydrate.

These days doctors are increasingly cautious about prescribing them, because they’re habit-forming, cause respiratory depression, and long-term use is associated with cognitive impairment. However, despite its complicated medical history, diazepam is a useful example for carbonyl chemistry. Let’s focus on one part of its synthesis, involving the top bit of the molecule with the chloroacetate.

A likely mechanism starts with the carbon attached to the chlorine being attacked by nucleophilic ammonia, replacing the chlorine with NH2 in an SN2 reaction. After that, you’ll notice, we have an amine nice and close to a carbonyl group! That carbonyl group is irresistible to the nucleophilic nitrogen, and it attacks, forming the imine that is part of diazepam.

This intramolecular reaction closes the seven-membered ring that's a signature part of this family of medicines. Overall, in this episode we’ve learned that:. Aldehydes can form hydrates in water, and formalin is a particularly important example.

The two anomers of the hemiacetal form of glucose are connected by a reversible reaction between aldehyde and alcohol groups. Acetals can be a useful way to protect carbonyl groups in longer syntheses. And imines and enamines can be formed from aldehydes and ketones.

That’s it for aldehydes and ketones for now, but we definitely haven’t seen the end of these important functional groups – they’ll pop back up here and there! Next episode we’ll explore another kind of carbonyl-containing chemical: the carboxylic acid. Until then, thanks for watching this episode of Crash Course Organic Chemistry.

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