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Ch. 14 - Synthetic TechniquesWorksheetSee all chapters
All Chapters
Ch. 1 - A Review of General Chemistry
Ch. 2 - Molecular Representations
Ch. 3 - Acids and Bases
Ch. 4 - Alkanes and Cycloalkanes
Ch. 5 - Chirality
Ch. 6 - Thermodynamics and Kinetics
Ch. 7 - Substitution Reactions
Ch. 8 - Elimination Reactions
Ch. 9 - Alkenes and Alkynes
Ch. 10 - Addition Reactions
Ch. 11 - Radical Reactions
Ch. 12 - Alcohols, Ethers, Epoxides and Thiols
Ch. 13 - Alcohols and Carbonyl Compounds
Ch. 14 - Synthetic Techniques
Ch. 15 - Analytical Techniques: IR, NMR, Mass Spect
Ch. 16 - Conjugated Systems
Ch. 17 - Aromaticity
Ch. 18 - Reactions of Aromatics: EAS and Beyond
Ch. 19 - Aldehydes and Ketones: Nucleophilic Addition
Ch. 20 - Carboxylic Acid Derivatives: NAS
Ch. 21 - Enolate Chemistry: Reactions at the Alpha-Carbon
Ch. 22 - Condensation Chemistry
Ch. 23 - Amines
Ch. 24 - Carbohydrates
Ch. 25 - Phenols
Ch. 26 - Amino Acids, Peptides, and Proteins
Ch. 26 - Transition Metals
Synthetic Cheatsheet
Moving Functionality
Alkynide Alkylation
Alkane Halogenation

Here will we go into more depth about moving functionality which is important if you want to move non-alkane functional groups on a molecule. 

Concept #1: Moving Functionality in Synthesis


The synthetic cheat sheet talked a lot about moving functionality from one atom to another and that's what I want to focus on in this page. I just want to focus on some practice problems of figuring out which direction to go and how to move these things in real life.
This chart is the same exact one from the cheat sheet but let's go ahead and fill it in really quick. So remember that – let's do our eliminations first. What kind of base would be favored for Zaitsev elimination? Small and strong. And then for a Hofmann? It would be bulky. Remember that? Then for the Markovnikov alcohol, Markovnikov alkyl halide. The alkyl halide is easy. That would just be HX. For Markovnikov alcohol, the one that we usually use is just HA over H2O, but we can also use oxymerc. I'm just going to write it down. We can also use oxymerc if we want to.
Then for the anti-Marks, it was the same deal, but I have to use HBr specifically over peroxides. And for my alcohol, for my anti-Mark alcohol, I would want to use hydroboration. I'm just going to write hydroboration because you guys are such pros at hydroboration. I'm just going to write here BH3.
So now we know kind of our road map and remember we said that if you start off with a alcohol, you need to do an elimination first. If you start off with a double bond, you need to do an addition first because it doesn't make sense – you can't add to something that's already added. You can't eliminate something that's already eliminated. So you have to alternate. That's what this just says up here.
What I want you guys to do for these practice problems is first of all the most important thing, honestly, is just identifying which direction do we want to go in because that's something that a lot of students aren't used to doing. And that's not something that professors really teach.
So for problem (a) go ahead and pause the video and just tell me is this going to want to go in the more substituted direction or in a less substituted direction. From that chlorine to that alcohol. So literally, pause the video and then when you're done, tell me if it's going to be in the more substituted or less.
All right. I hope that you said that it's going in the more substituted direction. Why? Because notice that I'm starting off with a primary and I'm ending up with a tertiary. That's all you need to do. That means I'm going in the more substituted direction.
So for (b), what direction am I going? Well, it's the opposite. I'm going from tertiary to primary, so this would be in the less substituted direction.
Does this give us a clue about what reagents we should be using here? Yeah, it does because it's like we have our whole blueprint right here. First of all, I know that I'm going in – for this red one, (a). I know I should be going in the more substituted direction, so I know I should be using the reagents from the top of my chart. I should be using either my Zaitsev elimination or my Markovnikov's additions. Cool so far?
On top of that, I'm starting off with an alcohol. So since I'm starting off with an alcohol, which one should I start with addition or elimination? I should start off with elimination. So check that out. It's telling me exactly what to do. I should use a small, strong base to do a Zaitsev elimination for my first step. Isn't that crazy because that's going to lead me to the more stable product – I mean, to the one that's more substituted. Isn't that crazy?
I just want to show you guys how it's like a roadmap. This is such an awesome chart. Let's keep going. Why don't we do the first one together since this is just really good practice and I think it helps if you guys are listening to the way that I think about it.
We just said that for my first step, I should use a small, strong base, that's a Zaitsev base, so let's go ahead and in this case, I actually don't have the choice between Zaitsev and Hofmann. Notice that I only have one elimination product possible and that's this double bond right there.
So I should just do whatever's going to give me the highest, the most amount of elimination product, not the most Zaitsev. So what that means is that I should actually use a bulky base because my small bases might do an SN2. For example, oxides. Oxides will do an SN2 if it's primary.
Let's actually just use LDA for my first step. What that's going to do is that's going to give me a molecule that looks like this. So now I have that. So now am I still trying to go in the more substituted direction. Yeah. I'm still trying to go towards that tertiary. So I should still be looking at the top of my chart. I should be looking at the more substituted direction right now. Let me make it in red. So I should be going in the more substituted.
Since I'm starting with a double bond now, should I use addition or elimination? I should use addition. It's really up to you guys which one you want to choose. But I would prefer to pick – unless you can't have carbocation shifts at all, which happens sometimes, let's just pick HX because HX actually can shift and it's easy to eliminate.
So let's go ahead and just use HBr. Now if you couldn't shift at all, then you should use instead of HX, you should use oxymerc. Oxymerc is the one that you choose when you can't shift at all. So what that's going to give me now is it's going to give me a carbocation here that's then going to shift through a hydride shift to here. So what I'm going to get at the end of this step is I'm going to wind up getting a Br right there. Cool.
So now I've got a Br and I'm trying to figure out how to make that into this. Do I have a one-step way to do that? Do I have a one-step way to take that Br and make it into an OH? Well, maybe what you're thinking is SN2. Remember that SN2 reactions could swap out an alkyl halide and put something else there. But actually, that's not a great strategy. The reason is because SN2 can't work on a tertiary. Really, the best thing to do here is actually just let's eliminate and then let's add the alcohol.
So let's go ahead and go ahead and do that. So what we would do is we would – we could do any elimination we want because we're just trying to get that Markovnikov site, so we could just use any Markovnikov base, like NaOH for tertiary. And what that's going to give me is a double bond that looks like this. So now I have a double bond that looks like that. And then I could use an acid-catalyzed hydration to do my last step. So I could use basically H2SO4 over H2O and that would give me my last step, a Markovnikov alcohol. Right in the middle.
That was one way to do it. Notice that the amount of reagents that I used was LDA, HBr, NaOH and then H2SO4 over H2O. Not terrible. We did it in four. I'm going to write that down just so you guys have it. We had HBr. Then we had NaOH. Then finally, we had H2SO4 over H2O.
That was a decent synthesis. Was there a faster way to do it? Actually, there was. There was a faster way to do this and I wanted to see if you guys would see it or not. A faster way to do this – both are right. One of them is better, though. Would have been, yeah, I'll do LDA from the very beginning. And that would still give me this double bond here. But then instead of doing HBr, at the end what I wanted was an alcohol anyway. So how about instead of doing HBr, I just did my acid-catalyzed hydration. So I did H2SO4 and water.
What you'll notice is that, that gives you – what does that give you? Well, that's going to give you a carbocation here and that's going to shift because of a hydride to here. So I'm going to wind up getting a carbocation here and then that's when my water attacks. So actually, my water could have just gotten there in two-steps. I could have just used LDA and the H2SO4 over H2O. So both of them worked.
And that's the thing about retro-synthesis, a lot of times you're going to have several options available to you to get something done. The better one is going to be the one that happens in the less steps. So the one that we should really pick is this one. That's the better one. Cool.
I hope that you guys just saw how we can use this flow chart basically – not this flow chart, but kind of like this guide, to figure out are we going more substituted or less substituted and then what's kind of our goal.
So now we're going to go to B and I want you guys to do this one all on your own and figure out how to go from the more substituted to the less substituted, so maybe you should be looking at the other part of the guide. And I'm going to let you guys try to take care of it and then I'll answer it for you. So go for it. 

Concept #2: Propose a Synthesis


Alright so for this one I'm going in the less substituted direction but at the very beginning I have an alcohol so I actually have to do an elimination reaction and at the very beginning I actually want to go in the more substituted direction, OK? The reason is because notice that if I eliminate this alcohol, OK? I'm either going to make a double bond here that would be Di-substituted or I would make a double bond here that would be tri-substituted, going in the tri-substituted direction actually gets me closer to where I need to go which is the less substitute direction so what I want to do is actually use a more substituted elimination first and then later on do the less substituted ones, OK? Now we have one more kink in this which is that I have an alcohol, is alcohol a good leaving group? No, it's not so you actually if some of you guys put like LDA don't write this LDA or tert butoxide those actually won't work on alcohol at all because alcohol isn't a good enough leaving group so what we need to do for this first part is well there's a few different things you could convert it to a good leaving group which is something that we haven't really done a whole lot of so I'm not going to do that but we could do is just we could do it an acid catalyzed dehydration, OK? So in my first step what I could do is just do HSO4 over H2O

and what that's going to do is that's going to give me a carbocation here and eliminate this direction in the Zaitsev direction so what I would get for the first step is something that like this, OK? Now I just want to point out that we can actually add this to our flow chart, OK? Zaitsev works small and strong works if it starting with an Alkyl Halide but if it's starting with an alcohol then I actually would want to use I'm going to put here base but if it's starting with an alcohol then I would actually want to use H2SO4 over H2O, OK? Because that's going to give me a Zaitsev elimination that actually works on alcohol, OK? The strong small base only works on Alkyl Halides, OK?

So I just have one more thing to add to your chart, OK? So now we've got this double bond and I'm trying to get this double bond to look like to get this chlorine over here, OK? So my question is OK I have a double bond so should I add next or eliminate next? I have to add, OK? So I have to add and in this case, should I add anti-markovnikov or markovnikov, should I add to the blue or to the green? I should add to the green because that's what's going to get me closer to where I need to go so let's go ahead and do a radical Hydrohalogenation and add a BR right here, OK? That's getting me really close so now I'm going to put here that my reagent was HBR over peroxide, OK? So now I have an addition should I do an elimination or another addition? I have to do an elimination, OK? Well what kind of elimination do I want? Do I want it to be a Zaitsev elimination in blue or a Hofmann elimination in red? I want this to be a Hoffman elimination so I get closer to the CL so what reagents can I use for Hoffman elimination? See now we're just going to anti you're going to do it less substituted all the way so I would use a bulky base, OK? So let's go ahead and use a bulky base let's do LDA that's just like the bulky base we're using a whole lot today so what that's going to do is that's going to give me a double bond...Oops that's going to give me a double bond that looks like this and we are oh so close, OK? We're really super close all we need to do is we need to get a chlorine on that position now it turns out that is the Markovnikov position or anti-markovnikov position what do you guys think? That's anti-Mark again so what we can use is HBR and peroxides, now it turns out you guys might be wondering why not HCL Johnny just put the chlorine right on there? It turns out that this reaction is only favorable with HBR So unfortunately, I can't use HCL so what that means is that I'm going to get a reagent a part that super close to the end product but it's going to look like this instead BR, OK? So now that I've got basically the same exact thing do you guys know of a way that I can change that BR for a CL? I could just do an SN2 so in this case I could just take the negative charged chlorine so step five would just be CL minus and CL minus could do a backside attack and kick out the bromine and then I would finally get my end product which would be this, OK? So I know that's a lot to take in but I'm just trying to show you guys how grouping reagents by more substituted direction less substituted direction can really help, OK? So now I want you guys to do one on your own very similar try to figure out the direction I'm just going to give you a hint right now it's both, OK? The direction this is like kind of a trick where at some parts the direction is going to be more substituted in some parts the directions is going to be less substituted it's your time to figure out what's the easiest way to make this happen it's actually not a very hard reaction to do it's not that many steps but go ahead and try to figure it out and then I'll give you the answer in just a sec.

Concept #3: Propose a Synthesis


Alright so for this first one we had to eliminate first because we have an addition product and it actually doesn't matter which direction because they're both exactly the same so I'm just going to do something to eliminate let me just use NaOET, OK? It's a strong enough base and what that's going to induce is a double bond that looks like this and I'm going to try to draw small I'm going to get a double bond that looks like that, OK? So now that I have NaOET the next step is do I want to add or eliminate? I want to add; do I want to add markovnikov or anti markovnikov? More substituted or less? Well ideally this bromine notice that it's on this branch, right? And that branch is attached to a tertiary carbon so ideally, I want to get closer to the tertiary carbon so that I can then get closer to the branch so since I wanted closer to the tertiary that would be markovnikov, OK? So what's an easy way to add markovnikov? Hx so let's just use HI this time, OK? What H X is going to do is it's going to give me a carbocation here? Let me just draw it out It's going to give me a carbocation there which is then going to shift with a hydrate shift to here and then finally my I would attack here so now I've got an Iodine relatively close to where the BR is, OK? So now the question is I have my addition product what should I do next? I should eliminate but at this point I'm already at the most substituted carbon and now I'm trying to get a BR on this primary so do I want to go in the more substitute direction or less? Which one? I want to eliminate in the less substituted direction because now I want to go towards this little edge over here, OK? Now I want to go this way so if I want to go in the if I want to eliminate and if I want to go in the less substituted that means that I have to use a bulky base, so let's go ahead and use a bulky base since we've been using it all day let's just use LDA, OK? So what LDA is going to give me is that now I'm going to wind up getting A double bond right here in the edge, OK? Because that's the least substituted double bond and now we need to add, right? Well what do we add? We want to add a bromine; do you want to add it markovnokov or anti-markovnikov? Anti-Mark so in this case I would use HBR over peroxides and there you have it we would get our end product so we just made it in four steps and that was actually really the best we could do it's......That was a long distance to move for just four steps we actually did really well, OK? One of the reasons we were able to move so quickly in just four steps from basically moved, how many carbons? 1, 2, 3, 4 positions the reason we were able to do that is because the shift helped a lot the shift went in the right direction for us so it saves us a few steps, OK? But I hope that now you guys are getting the feel for this whole additional elimination thing it's so common, it happens all the time these questions might be a little bit harder than what you're going to see but still the whole principle of addition elimination is a big deal, OK? So let me know if you have any questions but if not let's move on.