We've done a lot of aldol condensations, and in particular we've looked at the mechanism in great detail. In this video we're going to think about doing things in reverse. So we're going to start with a retro-aldol reaction and see how that way of thinking can apply to retrosynthesis. And so let's start with cinnamaldehyde right here. And if we do a retroaldol reaction, the mechanism is pretty much the exact reverse of an aldol condensation.
And so if we add a base like sodium carbonate, we're going to form benzaldehyde and acetaldehyde. Cinnamaldehyde is the molecule that gives cinnamon its smell. And benzaldehyde smells like almonds. And so this is a pretty cool experiment to do.
You can start with a molecule that smells like cinnamon and end with a molecule that smells like almonds. Let's analyze our cinnamaldehyde starting compound here to see how how we would form those products. We know the carbon next to our carbonyl is our alpha carbon, and we know the carbon next to that is the beta carbon.
And so looking at the structure, we know that there's a hydrogen attached to our alpha carbon like that. So if we think about breaking this double bond, we can see this two carbon set up over here on the right for acetaldehyde, so those are the two carbons, and then this is the hydrogen that's bonded to that alpha carbon there. Looking at the structure again on the right, we know that there are two more hydrogens bonded to that alpha carbon.
And so therefore, if we're doing things in reverse, we could think about adding two hydrogens to this alpha carbon. So let me go ahead and draw two hydrogens right here. So I'm just gonna write H2. And then we can think about adding an oxygen to the beta carbon. So we can think about adding H2O.
I know there's already a hydrogen on that beta carbon, so I could think about this being the hydrogen on that carbon. And then if I add an oxygen to that carbon, that would be this oxygen right here. So just a way of thinking in reverse, adding water, breaking your double bond and adding an oxygen and two hydrogens is one way of thinking. about forming your product here.
Or you could think about the reverse. You could think about losing water from this portion and sticking these two fragments together to give your aldol condensation product. So once again, this way of thinking can be very useful. if you're trying to retrosynthesize something, so if you're thinking in reverse. So for example, let's say a question on a test was, show how you could synthesize this enone here.
So once again, we're gonna do the same kind of analysis. We're gonna find our alpha carbon right here. So this is our alpha carbon and this is our beta carbon. Alright, so attached to our alpha carbon, we know that there's a hydrogen right here.
So we're gonna think about breaking this double bond. Alright, so let's go ahead and draw a retrosynthesis. arrow here, so we're gonna break that double bond.
So on the left, we're gonna have our benzene ring. We're gonna have our carbonyl here. And then we're gonna have a hydrogen attached to this carbon, attached to our alpha carbon.
And remember, we're gonna add two hydrogens to our alpha carbon. So we're gonna add two hydrogens to our alpha carbon, and that would give us the ketone that we would need. Right, for our beta carbon, we know there's already a hydrogen attached right here, and so we're going to add an oxygen to this beta carbon on the left.
So it's just our way of thinking about it. So over here on the right, we're gonna have a, we're gonna have, We have our carbonyl, and then we're adding an oxygen. We're adding an oxygen right here.
And then we had that hydrogen, so let me go ahead and draw on that hydrogen in blue. And then we can go ahead and draw our ring. So we have our ring right here.
And then we have our nitro. retro group coming off over here. So just to check ourselves and make sure that this is the right way of thinking about it in reverse, if we take water from this portion and stick those two fragments together, then that would give us our conjugated enum. product over here on the left. And so that's again one way of thinking about how to do these sorts of problems.
And so if they wanted you to give some reaction conditions here, you could go ahead and draw what you would need. So you'd say, I need to start with this ketone, like this, and then I would also need an aldehyde, so I'm redrawing the four nitrobenzaldehyde product. So we have four nitrobenzaldehyde like this.
Alright, so this compound, this ketone, of course, is this compound right here. And then, 4-nitrobenzaldehyde here is the same one that we drew right here. So if you take those two, right, and you put them together, you should form your conjugated enone.
Because remember, thinking about your alpha protons, there are no alpha protons on our four nitro benzaldehyde. So this carbon right here doesn't have any alpha protons. So the only source for alpha protons would be this carbon right here. This is your only alpha carbon with alpha protons on it. So in terms of what else we would need, we would need a base.
To do our aldol condensation, so we could add something like sodium hydroxide as our base, and we could create a solution of sodium hydroxide and water, and then also ethanol. If you took this ketone and this aldehyde and used these reaction conditions, you should form this conjugated enone as your major product. And so that's how to synthesize it.
So once again, thinking in reverse. Let's do another one. This one's a little bit different because we don't have an enone or an enal as our target compound.
We have an aldol. as our target compound. But we can use the same kind of thinking.
We can find our carbonyl and identify the carbon next to that as being our alpha carbon, and then thinking about this as being our beta carbon. And we know that this is the bond that forms, so we can think about breaking this bond. And we know that we have a hydrogen on this carbon right here, so I'm just gonna see if I can stick it into there. So when I think about retrosynthesis, go ahead and draw draw my retrosynthesis arrow in here. So on the left, I can see on the left that I'm going to have this carbon, two, three, four, and five.
So I have these five carbons right here. So I'm going to go ahead and draw those in. we have our carbonyl and then we have our five carbons.
And then I already have this hydrogen in magenta. And we're only gonna add one hydrogen this time. So let me go ahead and draw on one hydrogen in green because this isn't the conjugated product.
We stopped at the aldol if you're thinking about it in reverse. And so we're not gonna add two hydrogens, we're only going to add one here. And so what else would we need?
So over here on the right, let's think about the fact that there is a hydrogen. So hydrogen attached to this carbon right here. And then how many carbons will we have for our other compound? One, two, three, and four.
So we need a four-carbon carbonyl, right? And there's a hydrogen attached to it. So a four-carbon carbonyl. So let me go ahead and draw that in. One, two, three, four.
And then we have this hydrogen in blue to it. And so now we've identified, right, thinking about it in reverse, what compounds we would need to form this aldol product. We would need this ketone. and this aldehyde.
But in terms of actually synthesizing the aldol compound on the left, we have to be a little bit careful about how to do it. We need to do a directed aldol addition here. So let's think about starting with this ketone. So think about starting with this ketone here.
So I'm gonna go ahead and redraw it. I'm gonna draw it a slightly different way. So that's this ketone right here.
And to that ketone, we're going to add LDA. So we're going to form a lithium enolate here. And once we've formed our lithium enolate, then we can add our aldehyde. So in the second step, we can add our aldehyde here. So we talked about this in an earlier video.
So we add our aldehyde, it's a four carbon aldehyde. So we're going to add butanol. And then that's going to give us a lithium alkoxide.
So we need to protonate the alkoxide. So in the workup, we can add some water here. And then we're going to add our lithium alkoxide.
And that would give us our aldol product. So that would give us this. So that is the way to synthesize our aldol products.
Let me go ahead and draw it in here. Alright, so we would form this. Okay, so a directed aldol addition. Let's do one more of this retrosynthesis approach, and let's think about how to make this molecule. So this is a little bit different than before.
Alright, but we can do our same steps. We can identify our alpha carbon, right, the one next to our carbonyl, and then our beta carbon is the one next to that, right? So we could think about breaking this double bond, right, and adding two. two hydrogens to our alpha carbon. So let's go ahead and do that.
So we're gonna break that double bond and add two hydrogens to the alpha carbon. So thinking about this in terms of retrosynthesis, we have a ring here, and then... Let me go ahead and draw this over here.
We would have two hydrogens over here. Let me go ahead and get some more room. Alright, so probably easier to think about adding your oxygen to your beta carbon first, so let's do that.
Alright, we know we're gonna add an oxygen to our beta carbon, so let's go ahead and put in our oxygen on our beta carbon. I'll do that in green. And then we're gonna think about adding two hydrogens to our alpha carbon. So we're gonna draw in our alpha carbon like that and we're gonna add two hydrogens. I'm gonna put those in green like this.
That just gives us a little bit more room. And then we would have our carbonyl like that. And then we would have. Make sure to count your carbons when you're doing these. So let's go ahead and show those carbons.
So this carbon right here is this carbon. And then this carbon is this one right here. And then this carbon, our carbonyl one, is right here.
And so you can see this is actually an intramolecular aldol condensation. So if you think about losing water right here and sticking those two fragments together, you would form this compound. on the left, and so this is a pretty cool reaction.
Alright, we could redraw this, alright, so on an exam, you might, I mean, you could draw it like that, but most of the time you would see it in a different conformation, alright, so you would see the compound looking like this. So let me go ahead and draw that. Alright, so identify your carbons.
Carbon in magenta is the one right here, alright, carbon in blue. is the one right here, and the carbon in red is the one right here, which has your carbonyl. And then we'll go ahead and make our alpha carbon right here green, so this carbon right here.
So this must have been your starting compound, and so if you add a base, you could convert you can convert this molecule into your target compound. And so once again, an intramolecular aldol condensation, and we'll talk in more detail about those in the next video.