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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 is an overview of the 3 synthetic techniques you need to know. Let's get to it! 


1. Alkane Halogenation 

2. Organometal Alkylation 

3. Alternating Elimination/Addition to Move Functionality 

Concept #1: Review of Cheatsheet


So it turns out that I could actually boil this entire chapter down to one page and that's actually what I tried to do earlier this semester. I spent a lot of time just tearing apart this chapter and thinking what's the shortest way that I could teach it. I got everything on one page. It was actually really impressive. I'm going to share that page with you now.
But obviously, I'm not just going to teach you one page. I'm going to give you an overview right here of the three synthetic techniques that you need to know for this chapter and then we're going to practice it a whole lot. I'm going to give you guys lots of practice problems and lots of application. Let's go ahead and get started. I'm going to teach you guys the three important rules for synthesis that you need to know.
The first rule, so I'm calling this the synthetic cheat sheet. Like I said, use this as your reference point for the whole chapter. The first thing is alkane halogenation. A lot of you guys already know this, but alkanes are unreactive. So if I want a functional group on an alkane, I'm going to need to halogenate it first. Do you guys remember what we used to halogenate alkanes? Radical reactions. So I could use something like Br2 over heat. That would be an example of selectively halogenating an alkane so that I can then functionalize it later.
So that's already functional, this is. But check it out. I could now do a bunch of stuff to it. I could substitute for that. I could do an SN2. I could eliminate. I could do an addition reaction. Now this is kind of like, I just drew it like this because it kind of looks pretty, but this is kind of not true. What you would do first is you would actually eliminate first and then you would add because addition reactions happen to double bonds.
So whatever, but I'm just saying that forming that first halogen is always going to be the first step anytime you start off with a simple alkane. If you're starting off with just cyclopentane, whatever you need, you're going to need to halogenate first. That's the first rule. Easy, right? Cool. Let's go onto the second rule.
The second rule is called organometal alkylation. Now, two important words. What is organometal and what is alkylation? Organometal is just any molecule that is part carbon and then part some metal and they are bonded together. An example of that that you're very familiar with is a sodium alkynide. A sodium alkynide would be an organometal because I have a carbon with a negative charge and then I have a sodium with a positive charge. In this case, I didn't draw them bonded together, but they're associated with each other. So that's an example of an organometal. Cool.
Well, there's other types of organometals too. There's also this one right here that you don't know very well, but that's a Grignard. Later on, we're going to use that. But for right now, just keep in mind that both of these count as organometals.
Organometals are very strong nucleophiles because they create negative charges on carbon. It turns out that if you're ever trying to do a synthesis and you're trying to add carbons to a chain. Let's say you start off with a four-carbon chain and you need a five-carbon chain or you need a ten-carbon chain, what are you going to do? The only way that we can add carbon-carbon bonds in organic chemistry one is through organometal alkylation. That means reacting these with something that's going to add alkyl groups with an electrophile.
So what electrophiles do we have? Well, we have two common electrophiles. But one of them we're going to use a whole lot more in this chapter and that's alkyl halides because remember that alkyl halides do the opposite. Instead of putting a negative on the carbon, they put a partial positive on the carbon, so that's perfect because then what that means is the negative from one carbon is going to be attracted to the positive from another carbon and they're going to link up and that's what we call an alkylation. Pretty easy. It's just whatever that alkyl group is, it gets added on. The X leaves as a leaving group.
It turns out that a carbonyl is also very common electrophile because that has a strong dipole pulling away from that carbon, so it also places a very strong partial positive on this carbon. Now we're not going to deal with this one a whole lot in this chapter, but I still want you guys to hold on to this and realize that there's more than one nucleophile, there's more than one electrophile.
All of these, these are the big four. These big four are really important when it comes to making carbon-carbon bonds. The ones we're going to deal with mostly today are the sodium alkynides and the alkyl halides, which you already should have experience with. So that's not so bad. That's another very important rule. Any time you're adding carbon, think sodium alkynide, think organometal.
Then what's the last thing? The last thing is probably the most useful of the three. What it is is that moving functionality. There are many, many times in organic chemistry that I have a functional group in one place and I'm trying to get a functional group in a different place. I'm trying to go from one place to another. It doesn't even have to be the same group. It can be an alcohol here and it could be a sulfur over here. Whatever. The main point is that if you're trying to move one functional group from one place to another, then there's really only one way to do that and that's by doing alternating elimination and addition reactions.
Elimination and addition, as you guys know, are opposites of each other. They're opposites, since they're opposites that means that they can kind of undo each other's effects. So basically, what we do is we eliminate to make a double bond and that double bond will link two carbons together and then we add to the carbon that we want to go in that direction. And then we do it again. Then we add to that carbon, then we eliminate. Then we can do it again. By doing successive elimination/addition, elimination/addition, you could wind up moving the functional group from one part of the molecule to the other.
And we're going to do a lot of this today. But I just want to let you guys know, that really the only way to move functional groups. If you want to take functional groups from the right side and make it to the left side, you have to alternating elimination/addition.
Well, it turns out that anytime you're eliminating and anytime you're adding, you actually have a choice of which direction to go in because now you guys know how to do eliminations towards more substituted and less substituted and you also know how to do additions towards more substituted and less substituted. The thing is they had different rules. They had different names.
Remember that if you're eliminating and it's towards the more substituted location, that was called Zaitsev. Remember when you're adding and you're adding towards the more substituted, that's called Markovnikov. That's really important that you link those two together because both of those, the Zaitsev elimination, along with the Markovnikov addition, are always going to go towards or move towards my more substituted locations. So what that means is that if I can use reagents that are going to do Zaitsev eliminations and Markovnikov additions, I'm going to progressively move more towards the center of my molecule. The thing that's the most substituted. Does that make sense?
Whereas I have opposites of that. I have – if I want to go towards the less substituted elimination, I would do a Hofmann. That's the less substituted. If I want to move away from the center of the molecule to the less substituted addition, it would be an anti-Markovnikov addition. Does that make sense? So both of these you put together because both of these are going to favor the less substituted direction and these are going to favor the outside of the molecule. So I'm just going to put here the outside of the molecule and this one's going to favor the center of the molecule. Does that make sense?
What's so cool about this is that now, it's almost like I've given you guys two roads and you can choose which road to take based on what you're given. If you know you have to move – if you have a substituent that's all the way at the edge of a molecule and you need to move it towards the center, then we're going to start using a combination of addition and elimination, of Markovnikov and Zaitsev. Obviously, the opposite would be true if we're trying to move towards the edges.
Well, now all we have to do is we just need to figure out what are the actual reagents that we can use to do this. Let's start off with the eliminations first because those are the easy ones. If I want to just to a Zaitsev elimination, what kind of reagents favor a Zaitsev elimination? Do you guys remember?
In general, I'm just going to put here, a small strong, base. Small, strong bases favor Zaitsev. And really just examples, you can think of your own, but why don't you guys just start yelling out some examples of small, strong bases. Yeah. I think that you got that one. It would be, for example, NaNH2 is an example of a small, strong base. Also, NaH. Also, any of the oxides. Any OR- would be a small, strong base. Of course, not if you make the R group too big, but if you keep it small, that would be a small strong base.
And we can keep thinking of a few more. Well, even alkynides. Alkylnides are small, strong bases. In the right situations, they can favor that as well. These are all examples of bases that favor the Zaitsev elimination, so they're going to make the double bonds go towards the center of the molecule or towards the more substituted location.
Now if I want to do a Hofmann elimination instead, then what kind of reagents would I use? I'd use my bulky bases. Remember there were just a few bulky bases that you needed to know. I told you guys LDA, t-butoxide, and LiTMP. These are the really common ones that you need to be aware of. If it's not one of these, then you can pretty much assume that it's not bulky. Cool.
So now you guys – you guys already knew this, but now this is just helping you guys to solidify if I want to eliminate in the more substituted direction, I do Zaitsev, less substituted, I do Hofmann.
Now for additions, it turns out that addition is a lot more varied because elimination you just make a double bond, that's it. But for addition, you can either add alcohols or you can add alkyl halides. Obviously, there's other things we can do too, but these are going to be the two most common categories because a lot of times either an alkyl halide can be substituted for anything. You can just do an SN2 on it and an alcohol tends to be a very common reagent that we like to add to stuff. It just important to know the alcohol reagents.
Let's go ahead and write down these reactions. What if I'm trying to do a Markovnikov addition of alcohol. So now this is at the point where I'm starting with a double bond. I'm trying to do a Markovnikov addition of alcohol. What reagents could we use for that? This is going to help you categorize all the reagents.
Well, the reagents we could use would be, first of all, the easiest one would be just acid-catalyzed hydration, H2SO4 over H2O or any HA, any strong acid. So we know that that would work. Are there any other reagents that make a Markovnikov addition of alcohol? Oxymerc. This one's going to be a little bit bigger, but it's HgO(Ac)2 with water and then over NaBH4 and OH-. Cool?
So those are your two choices. I'm just going to kind of make a line there so you guys know that those are two different things. But those are our possibilities for Markovnikov addition. Why would I choose one over the other? Do you guys remember? What's better about one? Or why? I don't know. What's a situation that I would want to choose let's say, acid-catalyzed hydration? Why would I want to choose that? If I want a shift. If I want a carbocation shift. You can even write here positive. Just remember that would shift. Whereas oxymerc would never shift. So if you wanted a shift, that's not a good choice. Cool.
So how could I do a Markovnikov addition of an alkyl halide instead? This one's really easy. Think abut it. Markovnikov alkyl halide. I adding to a double bond. Just HX. HX is always going to do your Markovnikov addition of a halogen and it will rearrange and there's no equivalent of oxymerc for HX. There's no HX that won't rearrange, so just got to deal with it.
So that's if I'm trying to add substituents towards the more center of the molecule. But what if I'm trying to go towards the outside with my addition reactions? How about if I'm trying to add an anti-Markovnikov alcohol or an anti-Markovnikov halogen? Well, in that case, we would use completely different reagents. So what we would use here for alcohol, do you remember a way to make anti-Markovnikov alcohol? Yes, you do because remember it's my favorite reaction. So it would be hydroboration. It would be BH3 THF over H2O2 and NaOH. So hydroboration is the way that we would add an anti-Markovnikov alcohol.
What's the way if we wanted to make anti-Markovnikov halogen instead? Not alcohol, halogen. Well, then we could use a radical reaction because remember that HX is going to go Markovnikov unless we add peroxides. If we add peroxides then that makes it anti-Markovnikov instead.
Now, maybe it's making sense to you why I kept emphasizing guys, remember hydroboration and remember radical hydrohalogenation because I kept saying this is going to be very important for synthesis. Why? These are the only two reactions in orgo one that go anti-Markovnikov, so these are going to be the only two addition methods that you have to go outside towards the peripheral, towards the edges of the molecule. That's why it's really important.
So what's so cool about this chart is that yeah, a bunch of reagents aren't here. I totally get that. But the important reagents from moving functional groups are here now. What that means is that now as we're moving functional groups from one place to another, we can just use this as a cheat sheet and say which direction do we need to go? Is it more substituted or less? And then you figure out what to do.
Now also, you might be wondering, “Johnny, how do we know when to add? How do I know when to eliminate?” It's just whatever you're starting with. If you start off with a double bond. Let's say the question is turn this double bond into this functional group on the other side of the molecule. Well, then if you're starting with a double bond, your first step always has to be an addition. That means you would look towards the addition section and you'd say is this going to be a more substituted direction or less. That's the one you pick.
Then opposites true, if you start off with an alkyl halide or an alcohol, then you need to start moving it somehow, so you need to eliminate first and then once again, you'd look at your chart and say is it going to be eliminating in the more substituted or the less substituted. It's really awesome how it really turns into a formula once you have this in your mind. You start to think what can I do, what do I need to do instead of it just being a guessing game. Now you actually have a blueprint for what to do.
That was a really big intro of this sheet. Like I said, this basically summarizes the whole chapter. Now what we're going to do is we're going to do a lot of practice and I'm going to individually focus on each of these sections.
I hope that made sense. Let me know. But also, just wait it out a little bit in case you're confused because I'm going to go into depth on all three of these things. We're going to do a lot of examples.
Let's go ahead and move on.