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Hi! I’m Deboki Chakravarti and welcome to Crash Course Organic Chemistry!

When you think of alcohol, you probably think of alcoholic drinks like beer, wine, or spirits. As we touched on in episode 22 when we talked about elimination reactions, the alcohol in all of these drinks is ethanol, produced during fermentation. And while ethanol is toxic in larger quantities, the amount in a few drinks just leaves you feeling a bit tipsy.

Ethanol is only one member of the alcohol family, though. The alcohol with one fewer carbon, methanol, can cause bigger problems if you drink it. In our body, it’s oxidized into formic acid, which can damage the optic nerve, causing blindness and even death.

But alcohols aren't all toxicity and death. They can also serve a protective role in hand sanitizers, which usually contain ethanol, propanol, or isopropanol. Hand sanitizers affect the structure of proteins, causing them to become misshapen or ‘denatured.' They destroy the proteins that make up the outer shells of viruses and bacteria, killing them and preventing infections.

And in organic chemistry, alcohols are useful building blocks. In this episode, we’ll look at how we can use them as a starting point to get to other oxygen-containing organic compounds: ethers, epoxides, and more! [Theme Music]. We’ve already seen a few ways to make alcohols.

Back in episode 16, we saw how acid-catalyzed hydration of alkenes can add water across the double bond. Markovnikov’s rule tells us that the proton adds to the carbon in the double bond with the most hydrogens attached. We also saw that, with certain special reagents, the opposite happens: the hydrogen ends up on the carbon in the double bond with the fewest hydrogens attached, and we get what’s known as the anti-Markovnikov product.

Another way of making alcohols that we saw back in episode 20 is using substitution reactions. For example, mixing a haloalkane with sodium hydroxide will cause the hydroxyl group to displace the halide ion. We can also create a diol (basically a double-alcohol) by using an alkene, like we saw in episode 17.

Reacting an alkene with the oxidizing agent osmium tetroxide initially produces an osmate ester, which can then be hydrolyzed by water to produce the diol. The hydroxyl groups are added to the same side of the double bond, so the product is what’s known as a syn diol. So, okay, we've clearly seen lots of different ways to make alcohols.

But what about if we use alcohols in chemical reactions? What happens then? Well, we’ve seen that hydroxide ions are excellent nucleophiles, but alcohols aren't so nucleophilic.

Their charge is neutral and the oxygen in the hydroxyl group holds tightly onto its electron pair. However, alcohols are weakly acidic compounds with a pKa around 16. So if we deprotonate an alcohol, we make an alkoxide, the negatively charged conjugate base, which is an excellent nucleophile.

Alkoxides can help us make a different oxygen-containing organic compound: ethers, which have an oxygen connected to two alkyl or aromatic carbons. Let’s start by looking at a general model of the reaction, which proceeds by an SN2 mechanism. The alkoxide displaces the halide ion, leaving us with an ether.

To get more specific, here's the synthesis of diethyl ether, which was used as a general anesthetic in the 1800s, before we figured out anesthetics that didn't make patients vomit quite so much. We start with ethanol as our alcohol and another reagent: plain old sodium metal or sodium hydride, which is a negatively charged hydrogen with a pair of electrons that can act as a base. The sodium hydride can deprotonate ethanol, generating an ethoxide ion.

Then, we add the alkyl halide to the mix. And the lone pair of electrons on the oxygen attacks the carbon atom in bromoethane, booting out a bromide ion and forming diethyl ether. Great!

We’ve made an ether – so, now what? Well, actually, not a lot. Ethers are incredibly stable compounds, so it’s difficult to get them to do much in terms of chemical reactions.

The one thing we can do (besides using them as old-timey anesthetic) is break an ether back down using a strong acid and a substitution reaction. Here, the strong acid protonates our diethyl ether. Then, the lone pair of electrons on the bromide ion attacks the electropositive carbon atom attached to the oxygen, breaking the C-O bond.

So we have our starting compounds again: an alkyl halide and an alcohol. If we've got a lot of extra strong acid, our alcohol can also be converted to an alkyl halide through another substitution reaction with the bromide ion. So we're left with two alkyl halides at the end of this ether breakdown.

Converting alcohols to alkyl halides is actually a really useful tool for chemists. Remember that hydroxyl groups in alcohols are poor leaving groups because the hydroxide ion is a strong base. So if we can turn the hydroxyl group into a good leaving group, like a halide, we can make it more useful for other reactions.

There are three reagents we can easily use to convert alcohols into alkyl halides: hydrogen halides, phosphorus tribromide, and thionyl chloride. We just saw an example of a hydrogen halide, specifically, hydrobromic acid, protonating hydroxyl groups to break down a diethyl ether. And here's the basic model of this reaction with an alcohol.

The second option is using phosphorus tribromide. Here, the electron pair on the oxygen of our alcohol attacks the phosphorus atom, kicking out a bromide ion. The bromide ion can then act as a nucleophile and get a little bit of revenge: it swoops around and kicks out the oxygen that just bonded to phosphorus, which is a good leaving group.

That leaving group can then go on to react with two other alcohol molecules, going through the same steps! So, overall, one mole of phosphorus tribromide can convert three moles of an alcohol into three moles of an alkyl bromide. The final option for making an alkyl halide from an alcohol uses thionyl chloride, and only works for primary and secondary alcohols.

First, the alcohol and thionyl chloride react to form an oxonium ion intermediate. The chloride ion then attacks the carbon next to the oxygen, giving the electrons back to oxygen and neutralizing it. And there we have it, the alkyl chloride.

Most of the alcohol-to-alkyl-halide stuff we just did involved SN2 mechanisms, which flips the stereochemistry at chiral carbons. So if we add a nucleophile in an SN2 reaction later, we’ll get double inversion of stereochemistry. And we're back to the stereochemistry of our starting alcohol!

Now, if you're stuck with an alcohol, want to make it more reactive, and don't want to go with a halide leaving group… there are other options. For instance, you could use tosyl chloride or mesyl chloride to turn alcohols into tosylates or mesylates. In these reactions, the stereochemistry at the carbon attached to the hydroxyl group stays the same.

So, later, if we add a nucleophile and do an SN2 reaction on our mesylate, the stereochemistry of the starting alcohol is inverted. This isn't to say that making an alkyl halide is "better" than making a mesylate, or vice versa. A lot of organic chemistry involves multi-step reactions and carefully controlling products, so it's useful to know reactions that can do subtly different things.

Remember, the stereochemistry can have huge differences on the function of molecules, from smell to toxicity! We can also just tweak the structure of alcohols a bit to make epoxides, which are essentially cyclic ethers, where the oxygen forms a three-atom ring with two carbon atoms. If "epoxides" sound familiar, that's because we've seen how to make them from alkenes already.

But we can also make them from halohydrins: compounds containing a halide and a hydroxyl group on adjacent carbon atoms, which we learned to make in Episode 16. We come across epoxides in epoxy glues, where they react with amines to form an adhesive polymer. Epoxides are also important when it comes to organic synthesis, because they’re much more reactive than the very stable ethers that we could only break down with a strong acid.

Epoxides have a lot of ring strain, so they open up pretty easily. We can actually break open the ring in two ways, to form two different products, through an acid-catalyzed reaction or a base-catalyzed reaction. The acid-catalyzed reaction, which we also met in Episode 16, is an SN1-like reaction, involving our epoxide, an acid, and a nucleophile.

Having an acid means we have a bunch of protons floating around, so first the oxygen in the epoxide gets protonated. Then, we have an oxonium ion with a positive charge, which has resonance with two carbocations. So the nucleophile attacks the more substituted carbon, the one with better stabilized carbocation character, breaking open the ring.

And finally, there's one more deprotonation to give the final product. On the other hand, in the base-catalyzed reaction, there’s nothing to protonate the epoxide. We've just got our epoxide, and our basic nucleophile.

So the nucleophilic attack comes first. The nucleophile will attack the least substituted carbon – triggering an SN2 reaction and breaking open the ring. Then, we can add in some acid in a second step, and the negatively-charged oxygen grabs a proton, forming the final product.

Like I mentioned, the products of acid-catalyzed and base-catalyzed reactions are different, because these two reactions can have different regioselectivity. We don't have to think about it too much now, but this will be useful for multi-step reactions too! Okay!

We’ve just got one final set of alcohol reactions to cover: oxidations. Remember from episode 17, we can define oxidation as the loss of electrons– remember LEO the lion says GER? And we can also define oxidation in organic chemistry as the loss of carbon-hydrogen bonds or gain of carbon-oxygen bonds.

Alcohols can be oxidized using chromic acid, and the products we get are determined by the type of alcohol we’re starting with. Primary alcohols initially oxidize to form an aldehyde. But because chromic acid is a strong oxidizing agent, it will keep on going, oxidizing the aldehyde to a carboxylic acid.

If you’re starting with a secondary alcohol, you’ll end up with a ketone after the oxidation reaction. But if you’ve got a tertiary alcohol, you’re out of luck. Even a strong oxidizing agent won’t do the job.

Let’s look at part of the mechanism of alcohol oxidations to see why. As our example, let’s use benzyl alcohol, which we can see from the structure is a primary alcohol. This can be oxidized to benzaldehyde, the molecule that gives almonds their characteristic smell.

And benzaldehyde can be oxidized to benzoic acid, which is used as a food preservative. In the mechanism here, you can see that the oxidation reaction removes hydrogen atoms from the benzyl alcohol molecule, which lines up with our definition of oxidation for organic molecules! Specifically, our starting molecule loses two hydrogen atoms to make the aldehyde – one from the hydroxyl group, and the other from the adjacent carbon.

So we can see why tertiary alcohols just won't oxidize! They don’t have any hydrogens attached to the carbon with the hydroxyl group, so they certainly can't lose two of them. Meanwhile, the chromium is reduced from chromium six, which is orange in solution, to chromium three, which is green.

This gives us a handy color change to indicate that oxidation of our alcohol has taken place. If oxidation hasn’t taken place, we won’t see a color change – easy as that. Okay, but what if you’ve got a primary alcohol you don’t want to oxidize all the way to a carboxylic acid?

This is where weaker oxidizing agents come in. Instead of the very strong chromic acid, we can use something milder like pyridinium chlorochromate and pyridinium dichromate to stop at an aldehyde. The downside of all of these oxidizing reagents we've looked at is that they contain chromium.

It's good for that handy color change I mentioned, but chromium compounds like chromic acid and dichromate salts are toxic, carcinogenic, and corrosive – in other words, not great to be using regularly. But there are some safer mild oxidants that can be used instead, such as Dess-Martin Periodinane (or DMP). So it's safe to say that alcohols are way more than just beer and wine, they're involved in lots of important reactions and make compounds with specific reactivity, stereochemistry, and regiochemistry.

We'll be seeing plenty more of them in future episodes. In this episode, we:. Reviewed the reactions we know to form alcohols.

Looked at substitution reactions that can make alcohols into better leaving groups. Learned how to open epoxides regioselectively, and. Oxidized alcohols to aldehydes or carboxylic acids with different reagents.

In the next episode, we’ll take a break from adding more reactions to our toolkit and apply some of what we’ve learned to a lab experiment! 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.