Chemoselectivity and Protecting Groups | Organic Chemistry

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[00:00:07]Hi! I’m Deboki Chakravarti and welcome to Crash Course Organic Chemistry!

[00:00:10]We’ve gathered a pretty impressive toolbox of chemical reactions, and can use them to transform a lot of functional groups we might come across.

[00:00:18]But as we meet more complex molecules, we run into a problem: in addition to the bits of molecules we want to react, we find that other bits start reacting too!

[00:00:29]Imagine for a second you’re going to paint a room in your house (like maybe purple and yellow, to turn your office into a remote set for Crash Course) If you’re being careful, you’ll use painters’ tape to cover up the edges of window frames, light switches, or decorative trim.

[00:00:45]Once you’ve finished painting, you peel off the paint-splattered tape, revealing those pristine old surfaces in your otherwise new room.

[00:00:51]And we can do this with molecules too!

[00:00:54]We can prevent a functional group from reacting by "taping over" it before we throw a bunch of reactants at the molecule.

[00:01:01]Then we remove the "tape" at just the right moment, so our original functional group remains in the otherwise new molecule.

[00:01:07]This painters’ tape for chemical reactions can go by many metaphorical names, but it's technically called a protecting group.

[00:01:14]In this episode, we’ll learn how we can use protecting groups to control how our molecules react.

[00:01:19][Theme Music] In episode 32, we saw how we can reduce carbonyl compounds using metal hydrides.

[00:01:35]This is really straightforward if we have a molecule with just one carbonyl group.

[00:01:40]But say we’ve got a molecule with more than one carbonyl group, and we only want to reduce one of them.

[00:01:46]Then, things get a bit more complicated, because reducing agents will reduce the more reactive functional group fastest.

[00:01:53]So if we want to reduce only the less reactive functional group… we run into a problem.

[00:01:59]We looked at the reactivity of carboxylic acid derivatives in the previous episode.

[00:02:04]Let’s add in the other carbonyl compounds we’ve encountered to give us the full picture: As an example, this molecule has two carbonyl functional groups: a ketone and an amide.

[00:02:14]If we use a reducing agent like lithium aluminum hydride, that reactivity comes into play.

[00:02:19]The ketone gets reduced first into an alcohol, and then the amide gets reduced into an amine.

[00:02:25]Lithium aluminium hydride is pretty much the sledgehammer option for reducing carbonyl compounds, as it can reduce them all.

[00:02:32]It can even reduce the less-reactive carboxylic acids, albeit more slowly.

[00:02:36]If we want a bit more nuance, though, we can select a different reducing agent, like either lithium or sodium borohydride.

[00:02:43]Lithium borohydride can reduce aldehydes and ketones pretty quickly, or esters more slowly.

[00:02:48]Sodium borohydride can reduce aldehydes and ketones, but it’s speediest with aldehydes.

[00:02:54]Taking that molecule with two functional groups from before, sodium borohydride would be the perfect choice if we want to reduce the ketone, but not the amide.

[00:03:02]But none of these reducing agents will help us reduce the amide but not the ketone.

[00:03:07]To stop the ketone from reacting, we need to cover it in our chemical painters' tape: a protecting group.

[00:03:13]Except because protecting groups can look really different depending on what they're covering, or which reactant they're hiding from, it's more like giving the ketone a unique chemical disguise.

[00:03:23]With sunglasses and a fake moustache, our ketone is unrecognizable to lithium aluminum hydride and they don't react.

[00:03:30]The ketone can slip past the reducing agent undetected, and take off the disguise once the reaction is complete!

[00:03:36]Mission accomplished.

[00:03:38]As we know from spy movies, there are both elegant and bad disguises – and the same applies for chemical disguises.

[00:03:45]There's a three-part checklist for a good protecting group: 1. It needs to be easy to attach to the part of the molecule we want to protect.

[00:03:53]We want to avoid multiple additional reactions or using inconvenient reaction conditions.

[00:03:58]Just like we want to smoothly change into a new spy outfit, not fumble around with an ironing board before swapping shirts.

[00:04:05]2. It shouldn’t react under the conditions we need to use later in the reaction, because that might make it more difficult to remove afterwards.

[00:04:13]Just like we need a disguise to work in all locations.

[00:04:17]Traditional army camouflage is great in a forest, but not so great if we have to swim in the ocean too – then our clothes are heavy and damp and a pain to change out of.

[00:04:26]3. It needs to be easy to remove, without affecting other groups in the molecule.

[00:04:31]If removing it requires a reaction that will change other functional groups in the molecule, we'll get a headache trying to change them back!

[00:04:37]Just like we want our fake moustache to come off easily, and without leaving incriminating glue marks or synthetic hair all over our clothes!

[00:04:44]For example, one way to protect aldehydes and ketones is to turn them into an acetal group.

[00:04:50]We met the acetal group in Episode 29 when we added methanol to a ketone.

[00:04:55]This group protects aldehydes and ketones from reactions with nucleophiles and bases, and the diol makes a cool little ring structure.

[00:05:02]With our protecting group in place, we can go ahead and react our amide with lithium aluminium hydride to convert it to an amine: So far, so good – our protecting group was easy to put in place, so that's one check mark.

[00:05:15]And it hasn’t reacted under the reaction conditions used to reduce our amide, so that's another check.

[00:05:21]All we need to do is add acid to hydrolyze our chemical disguise away – so it checks the final box of being easy to remove, too!

[00:05:27]Let’s take a closer look at this removal mechanism.

[00:05:31]One of the oxygens in the acetal group grabs a proton, which leads to one of the oxygen-carbon bonds breaking with a push from the neighboring oxygen.

[00:05:39]Next a water molecule swoops in, kicking off a chain of proton transfers and electron movement, which eventually forms an oxonium ion.

[00:05:47]Then, a final water molecule plucks the hydrogen off of the oxonium to remake the ketone.

[00:05:52]So, with help from an acetal protecting group, we can reduce a carbonyl group even if it’s less reactive than other carbonyl groups in the molecule.

[00:06:01]We don't just use chemical disguises with carbonyls, though.

[00:06:04]Take a look at this reaction: we want to remove the bromo functional group on the right-hand side of the starting material, and replace it with an additional alcohol and phenyl group.

[00:06:13]Let’s start by comparing the number of carbons in our starting material and product to see where we need to form a bond.

[00:06:18]If we can transform our starting reagent into a Grignard, we could hypothetically use it to join onto an epoxide like we learned in Episode 24.

[00:06:26]But wait – there’s a problem.

[00:06:28]Grignards will react with alcohols in an acid-base reaction!

[00:06:32]So as soon as we form the Grignard, we won't get the reaction we want.

[00:06:36]Our Grignard molecule could react with itself, deprotonating the alcohol group on the other end, or it could react with another reactant molecule.

[00:06:44]Either way, we're nowhere near the product we wanted to make.

[00:06:47]So we’ll need a protecting group!

[00:06:50]And there are two classic chemical disguises that alcohols can use.

[00:06:53]One option is silyl ethers, with a silicon atom covalently bonded to an alkoxy group.

[00:06:59]There are a few different varieties with different alkyl groups attached, but the one we’ll use here is tert-butyldimethylsilyl ether, or TBS for short.

[00:07:08]So let's react our alcohol with TBS chloride and triethylamine, which will snag the hydrogen that’s on the OH group.

[00:07:14]The newly attached TBS protecting group can’t be removed by a base, and we can remove it later by reaction with fluoride.

[00:07:21]Smaller silyl groups come off easily in acid, but the chunky silyl ethers are a little more resistant and more commonly used in practice.

[00:07:28]A second protecting group option for alcohols is a benzyl group (Bn for short).

[00:07:33]We have lots of aliases for our disguised molecules, which help us from having to draw out big protecting groups in our reaction mechanisms.

[00:07:39]We can attach this protecting group by reacting the alcohol with a strong base like sodium hydride and a benzyl halide.

[00:07:47]The benzyl group has an advantage over the silyl ethers because it's not removed by bases, and it’s also tricky to remove in acidic conditions.

[00:07:55]However, it has to be removed by hydrogenation, which might be a problem if you have double or triple bonds in your molecule!

[00:08:02]For the Grignard-related reaction puzzle we were looking at, either of these alcohol protecting groups will do, but let’s just use a silyl ether.

[00:08:10]Before we form a Grignard or anything though, we need to add a protecting group using TBS chloride and triethylamine as our base again.

[00:08:18]TBS takes the place of the hydrogen on the alcohol group.

[00:08:21]And our chemical disguise was easy to add, so that's one of three checks on our "good protecting group" checklist.

[00:08:27]Now we can form a Grignard by reaction with magnesium.

[00:08:30]Our protecting group is disguising the alcohol, preventing those acid-base reactions we don't want.

[00:08:36]So not reacting under the conditions of the reaction: check.

[00:08:39]This means we can go ahead and form the product we want, by reacting with this epoxide!

[00:08:44]Again, the protecting group remains unchanged during this reaction: so... double check to that second box.

[00:08:50]Finally, it’s time to remove the protecting group with an acid or a fluoride – in this case, tetrabutylammonium fluoride, or TBAF for short.

[00:08:58]Our alcohol protecting group is easy to remove: check!

[00:09:02]Just in case you had doubts, there's the checklist proof that silyl ethers are good chemical disguises!

[00:09:07]In addition to carbonyls and alcohols, amines are another common secret agent… well, functional group.

[00:09:13]Amines pop up often in organic molecules, and their nucleophilic and basic nature means that they can easily get involved in unwanted reactions if we don’t disguise them!

[00:09:23]And we have three main choices here.

[00:09:25]One option is adding a carboxybenzyl group (CBz or Z for short) by reacting our amine with benzyl chloroformate.

[00:09:32]Later, we can remove this protecting group by hydrogenation or using a strong acid.

[00:09:37]A second option is di-tert-butyl dicarbonate, more commonly known as Boc anhydride.

[00:09:43]In the presence of a base, we add a tert-butoxycarbonyl (or Boc) group in place of one of the hydrogens on the nitrogen in the amine.

[00:09:51]And we can remove it easily by adding acid.

[00:09:54]We can look to our Mold Medicine Map and the synthesis of penicillin V for our third and final amine protecting group: a phthalimide.

[00:10:02]This protecting group prevents the amine from reacting with an aldehyde in an earlier step of the synthesis.

[00:10:07]In this step, it's being removed from our proto-penicillin structure.

[00:10:11]The removal includes swapping the amide-like linkages to make a sort of double amide side product.

[00:10:17]Plus, there's a bonus disguise in our Mold Medicine Map!

[00:10:21]We can protect carboxylic acids by bulking them up, subbing out the hydrogen on the OH group to form a tert-butyl ester instead.

[00:10:29]And this protecting group can be removed later with acid.

[00:10:32]Sheehan actually did this deprotection right at the end of the penicillin synthesis, before making the strained four-membered beta lactam ring.

[00:10:40]This ring is really sensitive to breaking open by hydrolysis, which is why penicillin was really difficult to isolate in the first place.

[00:10:47]That’s why Sheehan saved the ring closing step for last, and it just so happens to be the last thing we'll mention about protecting groups too.

[00:10:54]In this episode, we: Defined a checklist for a good protecting group, and Identified good protecting groups for carbonyls, alcohols, amines, and carboxylic acids.

[00:11:03]In the next episode, we’ll learn how to make a target molecule by working backwards, and head into the virtual lab again to remove reaction side products by taking advantage of solubility differences.

[00:11:14]Until then, thanks for watching this episode of Crash Course Organic Chemistry.

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