Alcohol Protecting Groups

Alcohols are highly reactive. This can be a problem if we want to react on some other part of the molecule. How can we guarantee that a reaction won’t take place at the alcohol? 

Concept: General features of Alcohol Protecting Groups. 

Video Transcript

Hey guys, so now let's talk about protecting groups. Protecting groups are reactions that are used to shield certain types of functional groups. In this case, I'm using the word moieties just means some kind of reaction region of the molecule from a reaction that's going to happen on another part of the molecule.
I know that sounds complicated, but basically what we're going to try to do is we're going to try to shield vulnerable functional groups from certain types of strong reagents. By definition, this has to be a completely reversible, easily reversible reaction. The reason for that is that you're supposed to be able to take the molecule off after the reaction is complete. So if you're not able to regenerate that vulnerable functional group at the end, that's not really a great protecting group.
Let me give you an example of why I might need something like this. Let's go ahead and look at this reaction. We've got an alcohol and an alkyl halide on the same molecule. First of all, that brings up our first point. You're only going to use a protecting group if you have more than one functional group on a molecule. If you only have one functional group, we don't care, you don't need to protect anything. But if you have more than one, then there may be some instances where you want to react with one and not the other and that's when you use a protecting group.
Let's look at this reagent. Our reagent is an alkynide. As you guys might remember, alkynides are good nucleophiles, but they're also strong bases. Is there anything – oh, that's supposed to be erasing. Is there anything that the alkynide could do to those functional groups? Well, in this case, what I'm trying to do is as you can see, my end product, I'm trying to make this alkynide perform a substitution reaction on the alkyl halide. In this case, this would be an SN2 reaction. So that's what I'm trying to make happen.
But notice that there's that other functional group of the molecule, the alcohol. Can alcohols react with alkynides? Actually, yes and they react through a different mechanism. They react through an acid-base mechanism because we know that alcohols have an acidic proton and alkynides are very strong bases. It turns out that this reaction will not proceed to completion. In fact, the alkynide will almost exclusively react with the OH and it will pretty much not react at all with the alkyl halide.
So if I do want this reaction to happen, is there any way to make it only react with the alkyl halide and not the alcohol? Well, scientists determined, you know what, alcohols are messing up a lot of different reactions, so if we can figure out a way to get rid of the alcohol for a few minutes, then run the rest of the reaction and then regenerate the alcohol, that would be really helpful. That's exactly what we're going to do with our protecting group. 

For example, the following substitution reaction has a major problem as drawn. Can you spot the issue?

Protecting groups are reversible reactions that temporarily block groups from reacting, so that we can transform other parts of the molecule.

Using t-Butyl Ethers

One way to protect alcohol is to form a reversible adduct with isobutylene via acid-catalyzed alkoxylation, yielding a temporary tert-butyl ether, which is completely unreactive.

Concept: Mechanism of t-Butyl Ether Protecting Groups. 

Video Transcript

So the first type of protecting group that you need to know and probably one of the more common ones is a tertbutyl ether protecting group. Now what this does is it adds an ether to the oxygen making it unreactive because if you guys remember or if you guys just – we've learned about functional groups in the past, alcohols participate in a lot more reactions than ethers do. What that means is that if I can turn my alcohol into an ether, it's going to be protected as long as it is an ether.
Now the reaction that we usually use for this is an acid-catalyzed alkoxylation. Just so you know, an acid-catalyzed alkoxylation is a lot like an acid-catalyzed hydration except that we're using an alcohol as our solvent. In this case, the alcohol actually comes from my molecule.
So let's go ahead and draw out this mechanism. We're going to react with a molecule called isobutylene which is just this four-membered hydrocarbon with a double bond. And what we're going to wind up getting is an ether. Let's figure out how.
In our first step, we're going to protonate our double bond through a normal addition mechanism. What this is going to give me is a Markovnikov carbocation. Remember that Markovnikov states that your carbocation goes in the more stable position. After I've done that, given the electrons to the O, what happens next. Well, not it's time for my alcohol to step in. My alcohol is actually going to wind up attacking that carbocation.
What I'm going to make is something that looks like this, where now I have a tertbutyl group on one side, the ring structure on the other. I still have one H and a positive charge. Now how do you think we could get rid of that positive charge? Smart. What we could do is we could use the conjugate of my original acid. So I'm going to go ahead and use the conjugate of my sulfuric acid. I'm going to deprotonate. And lo and behold look what I've got. I now have an ether instead of an alcohol.
Now, why do you think this might be helpful, having it look like that? Well, because it turns out that this ether that I'm looking at right here, is completely unreactive to strong bases like alkynides. Remember that I said an alkynide would react with an alcohol, it won't react with an ether. So now that means if I were to introduce my alkynide to this molecule after the ether's in place, guess where it's going to react? Not with the ether. The ether's protected now. This is my protecting group. That's my protecting group.
So now what's going to happen is the only thing that it can possibly react with is my alkyl halide through an SN2 reaction. So that's the advantage of protecting groups. They allow us to react with just the thing we want and to ignore the thing that we don't want it to react with.
Now you might be wondering, “Well, Johnny, what does the final product look like?” Well, what we would do at this point is that we could – after this reaction is over, we could remove the protecting group. Why is that? Because we said this reaction has to be easily reversible, right? So what that means is that see how this is drawn with a forward-looking arrow? Well actually, it would be truly in equilibrium. It wouldn't be just a forwards arrow.
So for example, here were I drew a forwards arrow here, that should really be, technically, it should be in equilibrium because we know that it's going to go forwards now, but we can make it go backwards later.
So after we do this step, how do we get it back to the original alcohol? Well, if adding our protecting group was step one, and if adding our alkynide was step two, then we have a third step. The third step is just to add mild acid, so I could just say H2SO4 and water. And what that's going to do is that's going to deprotect. Whenever you protect, you always have to deprotect.
What does deprotect mean? It just means that I'm going to take that ether completely off. Now I'm not going to show you the whole mechanism to deprotect, but you can imagine it's just the reverse mechanism of everything we've drawn to protect it. So what that means is that I would actually protonate the O first, then it would leave and then it would get protonated. The tertbutyl group would leave and then it would get protonated and eliminated.
I hope that makes sense guys. For the purposes of your test, you will need to know when you have to use a protecting group and when you don't. In terms of synthesis, your professor could ask you, how do I make this final product. And just using that one reagent wouldn't be enough. You would need to use – first you'd need to protect. Second, you could use your alkynide. Third, you would have to deprotect using acid and water.
I hope that made sense, guys. Let me know if you have any questions. If not, let's go ahead and move to the next topic. 

Using Silyl Ethers

Another group used to protect alcohols are silyl chlorides and ethers, who commonly are reffered to as TBDMS.


*TBDMS-Cl or TBDMS ether to be exact. 'TBDMS' just stands for tert-butyldimethylsilyl


Concept: Mechanism of Silyl Ether Protecting Groups. 

Video Transcript

Alcohols are so reactive that sometimes we want to react with another part of the molecule without actually interfering with the alcohol and this is a situation where you want to use a protecting group, OK? So now I want to talk about a type of protecting group called Silyl Ether protecting group, OK? So just you guys know there are two main ways to protect alcohols, you can use a t butyl ether protect group or a Silyl Ether protecting group you may have to learn one or both of these for your professor I'm only going to include the ones that your professor needs, OK? So if you're watching this video and fits in your playlist that means that your professor want you to know this one, alright? So Silyl Ethers I know they sound weird but it just means that it's something made with silicon, OK? It's a molecule made of silicon It looks a lot like an ether except instead of an O it's going to have an SI a silicon, OK? And these are used to protect, remember that the definition of protecting group is something that you can put on the molecule, protect and then take it off later, OK? So just so you guys know there's this weird reagent called TBDMS, OK? TBDMS you absolutely do not need to know what it stands for but you do need to know is that the most common Silyl chloride used in organic chemistry 1 to make a Silyl ether, OK? So just so you guys know this is the structure, TBDMS, OK? And I would advise knowing what the structure looks like, why? Because you need to know the mechanism for this, OK? So how does this work? Well basically what I want to do is let's say that I'm trying to get Alkyl halide, OK? But we know that some reagents that react with alkyl halides also react with alcohols, OK? For example strong bases, strong bases can do elimination on alkyl halide but they can also deprotonate an alcohol so how do we protect that? Well what we could do is you could you expose the alcohol to a Silyl chloride what's going to wind up happening is that this silicon has a pretty strong dipole pulling away from it so there's going to be a partial positive charge right there, you can use your alcohol to attack that silicon but now Silicon just it's like carbon it's actually right under carbon in the periodic table so silicon wants to have 4 bonds, OK? Right now by adding that bond to silicon we're making five so if we make a bond we have to break a bond is there an easy bond here to break? Hell yeah, we can break off the chlorine and cause it to kick out as a leaving group what that's going to give us is a molecule that looks like this where nothing's happened to my Alkyl Halide yet but now I have O-SI with the two methyl groups and the tert butyl group, cool so far? OK We've also got the H that's still present and a positive charge, OK? What we can now do is we can use the chlorine that got kicked off to deprotonate, OK? And what we're going to wind up getting HCl, OK? Because of the fact that we are deprotonating with the CL and we're going to get our protected alcohol, OK? So we got O then you got SI methyl methyl T butyl, OK? Now the reason that this is hopeful is because now if I were to expose this to a region that reacts normally with alcohol this thing will not react with alcohol this is unreactive which is the entire point of a Silyl ether this thing isn't going to do anything, OK? It's not going to react to anything so what that means is that now in the next step there's another step that we're going to skip here we could do whatever we want to this part of the molecule, OK? We could react this with a strong base, we could react it with I don't know a nucleophile or whatever and we would only react with this...Only reacts with the target functional groups and it would not react with the Silyl ether.

So now that's great we can do whatever we want to the alkyl halide but what happens when we want to get that alcohol back? Because that's the whole point of protecting group is you want to make sure you can take the silicon off and get that H back on, OK? Well then, we're going to use another reagent and that reagent is kind of weird it's a nitrogen with butyl groups, OK? So just if you guys want to see what that looks like it would be a nitrogen with four butyl groups, OK? 1 2 3 4, OK? That's going to give it a positive charge and then you're going to have a negative F associated with that, OK? And what's going to happen is that the fluorine from that molecule can wind up kicking out so this is after I've done my reaction to the bromine, OK? Now I'm in my last step I'm going to deprotect, this is the protecting step this is protect 1 is protect then 2 is react, you do your actual reaction, OK? Then 3 is deprotect and when you deprotect the way that the mechanism goes for that is that your F negative is going to wind up coming over here and attacking that silicon, OK? And then kicking out the O because the fact that you can't make that many bonds to silicon you can only react 4 so now we're going to get is something that looks like this where now I still own you know let's say that I reacted with that with that Alkyl halide and I did some kind of SN2 so now I have a nucleophile here, OK? Notice that all I'm doing is I'm saying that some kind of reaction took place where I had a bromine before and now I have something else, OK?

Well now in this last step what I would get is O negative, OK? So what can we do to make an alcohol? Remember there's HCl around, where did that HCl come from? The HCl came from the Cl earlier that deprotonated the H so now my alcohol my OH...I'm sorry my O negative is going to deprotonate HCL and what I get as my final product is my alcohol once again, OK? Now the reason this is so helpful is because now notice that I can target a specific functional group if I wouldn't have protected and deprotected then maybe my nucleophile would have actually reacted with the OH, OK? But since I protected it with a Silyl ether now I can do whatever I want to the other part of the molecule and then I can deprotect it and get that alcohol back, OK? So it's very useful reaction it's one that your professor may want you to know, OK? So what I want you guys to do now is try to do this yourself draw the whole mechanism and try to predict what's going to happen here notice that it's really the same thing we're going to protect, what are you protecting? The alcohol, right? Then you got to react this is up to you have to figure out what that reaction is and then you're going to deprotect, OK? What I'm interested in is that you can draw that mechanism and figure out what the final product is, alright? So go ahead and try to do that and then I'll jump in and I'll show you guys how solve it.

Example: Predict the product of the following reaction.