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You may know that cows produce methane, which is a big concern when it comes to global heating, but did you know that organic chemistry provides a potential solution to this problem? Feeding cows small amounts of red seaweed can greatly reduce methane emissions, in part due to organic chemicals called enols! In this episode of Crash Course Organic Chemistry, we’ll learn all about enols and enolates, their reactivity, and reactions we can do with them including halogenation and alkylation.

Episode Sources:
Cortney, C.H. and Krishnan, V.V., 2020. Keto–Enol Tautomerization of Acetylacetone in Mixed Solvents by NMR Spectroscopy. A Physical Chemistry Experiment on the Application of the Onsager-Kirkwood Model for Solvation Thermodynamics. Journal of Chemical Education, 97(3), pp.825-830.
Machado, L., Magnusson, M., Paul, N.A., de Nys, R. and Tomkins, N., 2014. Effects of marine and freshwater macroalgae on in vitro total gas and methane production. PLoS One, 9(1), p.e85289.
Machado, L., Magnusson, M., Paul, N.A., Kinley, R., de Nys, R. and Tomkins, N., 2016. Identification of bioactives from the red seaweed Asparagopsis taxiformis that promote antimethanogenic activity in vitro. Journal of Applied Phycology, 28(5), pp.3117-3126.

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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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. Cows produce methane, and that's a concern because of global heating. But their diet really affects how much methane they burp out.

In 2014, researchers showed that reading them a diet containing 1 to 2 percent red seaweed reduced their methane emissions by over 90 percent. The problem with this exciting research is that there's not enough wild seaweed to feed all the cows and this seaweed hasn't been commercially farmed yet. But people are working on it.

In the meantime, to better understand red seaweed, chemists have been looking closely at its chemical makeup. One of the minor components is bromoacetone, a substance that can be made in the lab by combining bromine with acetone in the presence of an acid catalyst.

This reaction works because the acetone enolizes in the presence of the acid. What does that mean exactly? Well, we're about to find out, as we dive into enols and enolates. 

[Theme Music]

If you're thinking that the word enol sounds familiar, it is! We first met enols in episode 18 when we learned about alkynes- molecules with a carbon-carbon triple bond.

Alkynes react in similar ways to alkenes- they undergo addition reactions. Makes sense if you think about it! There's a nice juicy electron-dense center where the triple bond is, so anything that's even a little electrophilic is going to head straight there.

A particularly important set of addition reactions involve water. Adding an OH group to an alkene produces a straightforward alcohol, but alkynes do something funky. We get a ketone,  Well, to be more specific we get an enol- a molecule with an alcohol attached to a carbon-carbon double bond. And the enol tautomerizes to a ketone.

 (02:00) to (04:00)

It's the same story if we carry out hydroboration-oxidation of an alkyne, except this time our enol tautomerizes to an aldehyde.

If you want to know more about these alkyne chemical reactions, check out episode 18. Because this episode is all about enols and their cousin enolates. We'll get to them in a bit.

Enols are tautomers, which is a word that comes from the Greek "tauto," "the same," and "meros," "part". Tautomers are a specific type of isomer where the only difference between the two compounds are the positions of the hydrogens and the electrons. The carbon skeleton is the same.

When I say skeleton, the carbon atoms are the bones. Even though a carbonyl and an enol might look different at first glance, they have the same basic structure of three carbons.

Bonds are just shared electrons, they're more like the tendons and muscles on top of the skeleton. When a carbonyl oxygen atom is protonated, we get an intermediate cation. Then, this intermediate loses a proton from its alpha carbon- which is the carbon adjacent to the carbonyl- creating a neutral enol.

We know this tautomerization happens because we can observe it with certain enols if we pop everything into an NMR spectrometer.

We can think of an enol as a type of alkene and because of the resonance electron donation from the lone pair on the oxygen to the pi bond, enols are more electron-rich and better nucleophiles than alkenes without an electron-donating group attached.

But we can make an even better nucleophile from something closely related to enols. Here's a useful organic chemistry rule of thumb: The conjugate base of a substance is always a better nucleophile.

Just look at water for example. Water is a nucleophile, but its conjugate base, hydroxide is a much better nucleophile. We talked about nucleophilicity in episode 21.

The conjugate base of an enol is called an enolate ion - and it has a resonance-stabilized negative charge. And enolate ions, which we often call enolates for short, are great nucleophiles!

To make enolates, we take a carbonyl compound- like a ketone- and add a strong base- like hydroxide ions. 

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Instead of forming a neutral enol, the ketone reacts with hydroxide to become a negatively-charged enolate. The key to this reaction are the hydrogens on the alpha-carbon. Remember, that's the neighbour to the carbonyl group. These alpha-hydrogens are acidic, while the other hydrogens in carbonyls aren't acidic enough to be removed by a base. When the alpha-hydrogen is deprotonated, the anion that forms is resonance-stabilized.

Let's look at the relative acidity of alpha-hydrogens in different molecules for a moment, because this is going to introduce fun new compounds. Remember, the lower the pKa value, the more readily the substance donates a proton, and the more readily an enolate will form. 

The pKa of the alpha-hydrogens in simple, alkyl-substituted aldehydes and ketones like acetaldehyde and acetone are in the high teens, but the pKa of the alpha-hydrogens in compounds with two carbonyls are lower, so those protons are more acidic, which makes sense, with two carbonyl groups flanking them to stabilize the negative charge in the anion. 

However, the alpha-hydrogens in esters have a higher pKa than their ketone cousins. This is because there's resonance donation from the oxygen of the alkoxy group towards the carbonyl. This makes the carbonyl more electron-rich already, and it's harder to stabilize an enolate.

And it's a similar story with amides: the nitrogen donates electrons to the carbonyl  through resonance, so, again, the oxygen of the carbonyl has quite a bit of negative character. The pKa of dimethylacetamide, or DMA, is a whopping 30. We're not going to get enolates very easily from these.

So, overall, if we react a carbonyl compound with an appropriate strong base, we get resonance-stabilized anions called enolates, which are great nucleophiles - even better than enols, which are pretty good themselves.

We can see the nucleophilic power of enolates if we look at halogenation reactions. Both aldehydes and ketones will react with a diatomic halogen like bromine at the alpha position, in the presence of a base.

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It doesn't even have to be a super strong base, because as soon as even a tiny bit of enolate is formed as an intermediate, the halogen reacts and uses it up. 

Remember LeChateliers principle? It's the idea that equilibria in chemical reactions shift to minimize the effect of a change, like a temperature change, or an increase or decrease in the amount of one of the substances. So when we use up the tiny bit of enolate that forms, it drives the equilibrium towards making more enolate, and the reaction keeps going. 

And here, we run into a little problem. The alpha-hydrogen on the now-halogenated carbonyl is more acidic than it was on the starting carbonyl. So it reacts, too. And, yes, the third hydrogen reacts as well. It's really hard to stop this halogenation reaction at the monosubstituted product.

Ok, so you might be thinking, why is this a problem? Maybe this triply-halogenated compound is fun, and cool, and useful? But the trouble is, in basic conditions, the triple-halogen product doesn't stick around. It's cleaved in something called a haloform reaction, and we end up with a carboxylic acid and a haloform, CHBr3

The most famous haloform is chloroform, CHCl3, which has all sorts of uses, from anaesthetic to solvent. So, haloforms can be interesting. In fact, bromoform is in that red seaweed from the intro, and it's thought to be one of the bioactive compounds that reduce cows' methane emissions. And this is great if we want a haloform, but not if our goal is to get a single halogen atom next to a carbonyl group. That's all messed up if we go about halogenation this way.

Thankfully, we almost always have options, like let's do our halogenation reaction in an acidic solution instead, using bromine in acetic acid. This reaction is much easier to control because there's no super nucleophilic enolate. We can just work with the slightly less nucleophilic enol.

Since we've got protons floating about, the carbonyl oxygen gets protonated. Next, the conjugate base of the acid nabs an acidic hydrogen from the alpha-carbon, giving us an enol intermediate.

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Like I said, this enol acts as a less aggressive nucleophile than our enolate last time. So, an electron pair attacks the bromine, and forms a resonance-stabilized cation. Finally, the carbonyl group loses its proton, and leaves us with the alpha-halogenated product we wanted - no out-of-control halogenations here. Yay!

Now, halogens are nice and all, but as you know by now, we organic chemists love to see carbon-carbon bond formation. If we introduce enolates to an alkyl halide or a tosylate, they undergo an alkylation reaction, joining the two smaller pieces into one bigger molecule.

What's happening is that the nucleophilic enolate ion is reacting with the electrophilic alkyl halide, in an SN2 reaction, and the leaving group is displaced by a backside attack. But, because of this, we run into the usual issues that we have with SN2 reactions - namely, the alkyl group should be primary, or methyl. This reaction isn't great with secondary alkyl groups, because we start to get a  competing E2 reaction - and with tertiary, the E2 reaction is all we get.

There's one more thing we have to look out for in these alkylation reactions with enolates. Because they're resonance hybrids, they kind of have a dual identity, and two different ways of reacting.

One part of the hybrid is a vinylic alkoxide - that is, a carbon-carbon double bond with a negatively-charged oxygen attached. In this situation, enolates react at the oxygen, and we end up with an enol derivative. But, the other part of the hybrid is the alpha-keto carbanion - that is, a carbonyl group bonded to a negatively-charged carbon. In this situation, enolates react at the carbon, giving us an alpha-substituted carbonyl.

We can often favour the reaction at carbon by carefully choosing our reaction conditions. But all these complications with enolates and alkylation could lead to something that really annoys chemists: mixtures of products. If only we had a more reliable way to add some carbons to our carbonyl...

Never fear, acetoacetic ester alkylation is here!

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This reaction effectively converts an alkyl halide into a methyl ketone with three more carbons, without so many potential side-products. As the name suggests, it involves acetoacetic ester, which is also called ethyl acetoacetate.

When we were comparing pKas, we saw that alpha hydrogens surrounded by two carbonyl groups are much more acidic than plain old carbonyls. So, this compound we have here is completely converted into its enolate ion when reacted with a base like sodium ethoxide. Next, that can be alkylated with an alkyl halide, making the carbon-carbon bond we know and love. In fact, because there were two acidic alpha-hydrogens, we can even do a second alkylation. If we want to add two different alkyl groups, we can perform the alkylations as separate steps, carefully adding one molar equivalent of base in each reaction. 

Now, we're not quite done, because this weird acetoacetic ester thing is hanging around in our product. Not bashing it - it was really helpful for this reaction, but we want a plain old ketone. And for that, we have to lose CO2 and the ethyl group from this molecule. So, we'll heat the alkylated or di-alkylated acetoacetic ester with some hydrochloric acid solution. Then, the ester portion is quickly hydrolyzed to a carboxylic acid, called a beta-keto acid, which loses CO2 in a decarboxylation reaction. These are easy to decarboxylate because when we lose CO2 from a beta-keto acid, the electrons have somewhere to go. We get an enol first, that tautomerizes into the more stable ketone.

And with that, we're done for now. In this episode, we learned that the alpha-hydrogens in carbonyl compounds are acidic, enols and enolates are good nucleophiles, we can carry out halogenation reactions with enols and enolates - but, enols are easier to control, and we can alkylate enols and enolates, and the acetoacetic ester alkylation is especially useful.

There's more enols and enolates coming up in the next episode, when we take a look at aldol and Claisen reactions, and turn to our mold medicine map of penicillin V synthesis.

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Until next time, 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.