Acetal Protecting Group

Now let's talk about a synthetic application of acetals and that's to use acetals as protecting groups. Let's look at these two molecules above me. What we’ll find is that these molecules are in equilibrium. We have learned word that if you expose a carbonyl to alcohol and acid, you can basically make an acetal. In this case since this is a cyclic acetal, I would expect to be using a cyclic diol in combination with acid. I’ll just put H+ to give me my cyclic acetal.
What's important about the difference between these is that there's a huge difference in reactivity between my original carbonyl and my acetal. Notice that my carbonyl has an extremely reactive partial positive pi bond. Whereas an acetal does have dipole so it does have dipole similar to the carbonyl. But notice that they're located on sigma bonds not on a pi bond. All of these bonds are extremely difficult to break. In fact, an acetal is about as reactive as an ether. Just remember how reactive ethers were. Pretty much unreactive. Ethers barely do anything. All that you can do is combust them. Sure, they blow up. But then others in combustion they don't react and that’s because these single bonds are extremely difficult to break.
If I ask you which one is the safer version, if I was to run a reaction somewhere else on the molecule, which one is safer to have around, a carbonyl or an acetal? The answer is an acetal because an acetal really isn't going to react with almost anything. Whereas a carbonyl is so reactive, we’ve learned they can even react with water, so we want to protect it. That's the whole idea behind a protecting group. Acetals are used to protect sensitive aldehydes and ketones from reaction with other reagents since they’re reversible. The idea being that you can turn the carbonyl in to an acetal, do your reaction somewhere else and when you're done, you can go ahead and hydrolyze it back to the original carbonyl, sparing it from reaction with your second reagent.
I want you to look at this example. I want you guys to devise a synthesis for this. I want you to look at these two molecules and figure out what would be the best way to make that first molecule into the second one. I’m going to give you a hint. This is not a one-step reaction. If you try to do it in one step, you’re going to fail. Try to think about what reactions you could and what sequence to make this transformation happen and then I'll show you. 

Alright, so the first thing you might have noticed is that actually switched the molecule on you guys by a little bit. I decided to put a nitrogen here instead of an O H. It's not really going to change the reaction at all, it's just that I did this for clarification because there were some unwanted side reactions with the O H that I'm trying to avoid. So anyway let's just look at this transformation, how could we make this happen? Well the transformation that I'm trying to produce is going from an amide to an amine and in case you don't remember this reaction or maybe you haven't even learned it yet the way to transform an amide to an amine is just to use a reducing agent, there's tons of reducing agents that will do this but I guess the most common is lithium aluminum hydride so we know that lithium aluminum hydride is a very powerful reducing agent and it's strong enough to get rid of that carbonyl and turn it into an amine.

So that's great to know, awesome, is that the answer for this question? No, I told you it's not going to be one step it's not that easy it's not you just put LAH and you're done but guys the reason is because LAH is a very powerful reducing agent and it's going to react with my ketone as well, I have a ketone, but look in the end product I need to also retain that ketone I can't just get rid of it and turn it into an alcohol so how can I reduce part of the molecule while keeping the ketone intact? You guessed it, we're going to use an acetal protecting group. So that means that before we do anything we're going to have to protect this ketone so let's go ahead and start. My first reagent is going to be, let's go ahead and use some kind of alcohol and acid to perform an acetal reaction. The most common protecting groups are usually the cyclic acetals, it doesn't have to be cyclic but that just seems to be the one that is kind of like the go to in the lab. So let's just use 1, 2 ethanediol which would be this guy. So it's a two carbon chain with two alcohols and acid, H plus. So what that's going to do is transform my ketone into an acetal so let's go ahead and draw that everything here is the same by the way, acetals don't react with amides so that's why nothing's going to happen down there but over here I'm now going to have O, O and two carbons in between. So that is my cyclic acetal protecting group, this is my protecting group. Cool, awesome guys, so now I've got my protecting group in place. What's awesome about these protecting groups is that, is that a very reactive molecule now? No, this is basically a diether and we know that ethers don't react much at all so now I can go ahead and reduce this molecule without fearing that I'm going to lose my ketone. So now let's go ahead to the next step, this is where I use my lithium aluminum hydride and that's just going to blast away at this amide. So what I'm now going to get is it's going to turn my amide into in an amine but I'm still going to have my protecting group in place.

Now one of the advantages of my acetal protecting group is that we know it's reversible so that means that what can I use to reverse it and take this off and make it back into the ketone? I can just use dilute acid, dilute H plus. There's lots of different ways you could write this, it could just H 3 O plus that's fine. So we know that instead of this being a one step reaction this is actually a three step transformation where one I placed my protecting group, two I used my reducing agent and then three I just used H 3 O plus to hydrolyse that acetal back off and regenerate the original carbonyl. Alright guys, so that is the way that we use acetal protecting groups. Let's go ahead and move on to the next page.