EAS: Retrosynthesis

All right guys, so now we're going to get some practice with proposing aromatic synthesis. So at some point in your course work you're going to be asked to propose an aromatic synthesis starting only from benzene or other benzene derivatives. You're going to have to turn that benzene into something more complicated.
In order to make this work, you're going to have to use your knowledge of sequence groups so that you can add the groups in the right positions. It's never going to be that easy that you don't need to use sequence groups.
Let's do this first example kind of as a worked example where I'm going to give you some hints and the second one you'll be completely on your own. For this first one, it says synthesize the target molecule from acetophenone and any other reagents. In this case, acetophenone is given to you as the molecule. But, you should be aware of what the name acetophenone means from the naming benzene area of our Clutch videos.
So what's going on here? What are the different transformations that are taking place? One thing that's happening is that I have a ketone that at some point needs to become a benzoic acid. So that's interesting. I've also got to add a nitro group in the para position so that's p, para substitution. So there's kind of a lot going on here. I've got a few different things.
One thing that I know for sure is that to put a nitro into the para position, at some point, my ketone is going to have to become what? An ortho, para director. Right now what type of director is it? Meta. Right now this is a meta director. If I were to nitrate this ketone right now, or this acetophenone, I would actually get a nitro here. Is that right? No. So I'm going to have to use my knowledge of sequence groups to figure out how can I turn that into an ortho, para director.
Now benzoic acid. Is this an ortho, para director? No, this is also a meta director. That means that I have to turn this into a benzoic acid sometime after I've added the nitro group because if I just turn it straight into benzoic acid, then I'm going to get a meta nitro group again. So this is kind of already outlining all the things we need to do.
So now I'm going to let you guys get creative. This is the part that I can't do for you. You just have to get creative with all the reactions we've learned and see if you can figure out the right sequence of reagents to make this final product. So go ahead and try your best and then I'll answer it for you. 

Alright so this was a three step reaction so if you got three steps you're on the right track the first step would be to turn this ketone into an ortho para director and we learned that we could do that through clemmensen reduction so my first regent would be a zinc mercury amalgam and what that's going to give me is in alkyl benzene I'm going to wind up getting specifically ethyl benzene. Now this is an ortho para director so since it's an ortho para director now I can use a nitration to put a nitro group in the pair position so I'm going to use H N O 3 and H S O 4 and that's going to give me my active electrophile which is going to attack the pair position predominantly and I'm going to get a nitro group. Why did I have to do a nitration next because now I have an ortho para director. Now do I have a one step way to turn this molecule into a benzoic acid? Yeah I do guys I can use K M N O 4 I can use another sequence group which is using K M N O 4 to oxidize the ethyl. Now remember that there's quite a few regents you have to write down so there's K M N O 4 which I mean some professors will be absolute fine with that but we have to be cautious. So the real the right way to write it would be K M N O 4 in the presence of base and heat and then I guess I said 3 steps it could technically be 4 but the way you could draw is you could also write like 3 A and 3 B since it's still the same reaction right so three B would be our acid H 0 + and what that's going to do is it's going to create a benzoic acid and that's our final product it does nothing to the nitro group so our final product ends up being this if we had to name it right it would be P nitro benzoic acid.

So guys I that was a good little introduction to sequence groups notice that there's no other order of regents that would've work I had to use those regents in specifically those borders because those are the specific sequence groups that I needed. Awesome guys so now you have another question go ahead and read it for yourself try your hardest and then I'll come in and I'll solve it for you.

Alright guys there was a lot going on in this question notice that pretty much the only thing that stayed the same was the ethyl group but a lot of other stuff changed. First of all I'm going to need to find a way to put a methyl group in the pair positions this is para substitution. Even harder than that I'm going to have to put it in an annulene in the ortho position so ortho substitution. Now I've got a few issues here first of all is ortho substitution very favored? In most cases no so the only way that I'm going to get a high yield of the ortho position is to make sure that this methyl group is there first or something is there blocking the pair position I need to block it so that it's going to be forced into the ortho. On top of that ideally this should be a meta director when I add the annulene because I want it to be synergistic with the ethyl group to face towards the top so we should be thing are there any groups that I can add that could be a meta director and then be turned into an ortho para director later, so that's one thing another thing is do we even know how to add annulene to benzene did I ever teach you how to add N H 2 specifically to a benzene an A E S reaction? No but did I teach you a precursor that can be easily turned into annulene? Yes guys remember reduction of nitro groups we can use nitration to make annulene which is why it's so popular, so at some point I need to nitrate that position but only after I already have some kind of meta director in this position, see where this is going alright you might not but let me just step in and try to help and guys this is just you have to just start getting a feel for these. So the first direction we're going to do is a friedel crafts acylation because we know that acylation can be turned later on into alkylation using a clemmensen reduction so I'm going to use I'm just going to erase this I'm going to use an acid chloride right. Now this part is important guys your acid chloride needs to contain the number of carbons that you want in your end product so since I'm adding it here how many carbon should this acid chloride have? Just one because I only have one carbon here that means that I should have an H on the other side because I only want one carbon total and that's the carbon on the carbon yield I'm going to combine that with A L C L 3 and I'm going to get a molecule that looks like this.

Now see so I got an aldehyde now notice that it attached to the pair position because we said that para is pretty much predominately favored especially when you have larger groups like the A silk groups cool. So now what can we do, well now I have a meta director here and an ortho para director here now is the time to nitrate because they're both synergistically pointing to that top position so now we would take my nitric acid and myself sulphuric acid and I would now make my nitrated my nitro group along with my aldehyde at the bottom, cool. Awesome guys so now what do you want to do? Well we have two more things we have to do, we have to do a clemmensen reduction and we need to do a nitro reduction. Now these you split slightly different regents so I'm just going to draw both of them and it doesn't really matter the order because both things need to happen and we don't have any more groups to direct so if you chose to do clemmensen first and then reduce the nitro that's fine or the other way around let's just do that so lets do clemmensen zinc mercury amalgam with H C L that's going to give me a single carbon with an N O 2 and then finally I would use you know any of my reducing agents that work on nitro groups to turn it into an annulene again I've told you a few times now I prefer stannous chloride S N C L 2 and H 2 O because that's the one that's chemoselective if there was anything else here that could be reduced it would only react with the nitro group and that's going to give me my final product. So this was a four step reaction and we got it we have figured it out. So you see how sequence groups are so important awesome guys so let's go ahead and move on.