Synthetic Cheatsheet - Online Tutor, Practice Problems & Exam Prep

In organic synthesis, three key techniques are essential: alkane halogenation, organometal alkylation, and moving functionality. Alkane halogenation introduces functional groups via radical reactions, while organometal alkylation utilizes strong nucleophiles like sodium alkynides to form carbon-carbon bonds. To relocate functional groups, alternating elimination and addition reactions are employed, with Zaitsev's rule favoring more substituted products and Markovnikov's rule guiding addition reactions. Understanding these principles is crucial for effective synthesis and manipulation of organic compounds.

Review of Cheatsheet

So it turns out that I could actually boil this entire chapter down to 1 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 can teach it. I got everything on one page. It was actually really impressive. So 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 3 of the synthetic techniques that you need to know. Okay? 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. Okay? So let's go ahead and get started. I'm going to teach you guys the 3 important rules for synthesis that you need to know. The first rule and so I'm calling this the synthetic cheat sheet. Like I said, use this as your reference point for the whole chapter. Okay?

So 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 use to halogenate alkanes? Radical reactions, right? 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. But check it out. I could now do a bunch of stuff to it. I could substitute for that. 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 like not true. What you would do first is you would actually eliminate first and then you would add. Since 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. So if you're starting off with just cyclopentane, you're going to need to halogenate first. That's the first rule. Easy. Right? Cool. Let's move on to the second rule.

The second rule is called organometal alkylation. Now, two important words. What is organometal and what is alkylation? Well, organometal just stands for any molecule that is part carbon and then part some metal and they're 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. See how they are associated with each other. That's an example of an organometal. 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 and organometals are very strong nucleophiles because they create negative charges on carbon. Well, it turns out that if you're ever trying to do a synthesis and you're trying to add carbons to a chain and you start off with a 4 carbon chain and you need a 5 carbon chain, or you need a 10 carbon chain, what are you going to do? The only way that we can add carbon carbon bonds in organic chemistry is to use common electrophiles, and one of them we're going to use a whole lot more in this chapter is alkyl halides. 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 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. Alright? Pretty easy. It's just whatever that alkyl group is, it gets added on. The x leaves the leaving group. It turns out that a carbonyl is also a very common electrophile because it 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. Alright? The ones we're going to deal with mostly today are the sodium alkanides and the alkyl halides. Alright? Which you already should have experience with. So that wasn't so bad. Right? That's another very important rule. Any time you're adding carbon, think sodium alkanide, think organometal.

So then what's the last thing? The last thing is probably the most useful of the 3. And 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 could be an alcohol here and it could be a sulfur over here or whatever. The main point is that if you're trying to move one functional group from place to another, then there's really only one way to do that. And that's by doing alternating elimination and addition reactions. Since elimination and addition are opposites of each other, they can kind of undo each other's effects. What we do is we eliminate to make a double bond and that double bond will link 2 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. And by doing successive elimination addition, elimination addition, you can end up moving the functional group from one part of the molecule to the other. We're going to do a lot of this today. But I just want to let you guys know, that's really the only way to move functional groups. If you want to take a functional group from the right side and make it to the left side, you have to do alternating elimination addition. Well, it turns out that any time you're eliminating and any time 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. So remember that if you're eliminating and it's towards the more substituted location, that was called Zaitsev. But 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 2 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. 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 less substituted elimination, I would do Hoffman. And if I want to move away from the center of the molecule to the less substituted addition, I would do 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. Does that make sense? So what's cool about this is that now, it's almost like I've given you guys 2 roads and you can choose which road to take based on what you're given. If you know you have a substitute all the way at the edge of the 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.

Now all we need to do is 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 do a Zaitsev elimination, what kind of reagents favor a Zaitsev elimination? Do you guys remember? So 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 you got that one. It would be like for example, NaNH₂ is an example of a strong small base. Also, NaH. Also, any of the oxides. So 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 alkanides. Alkanides 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. If I want to do a Hoffman elimination instead, then what kind of reagents would I use? I would use my bulky bases. And remember there were just a few bulky bases that you needed to know? And I told you gu

Here’s what students ask on this topic:

What is alkane halogenation and why is it important in organic synthesis?

Alkane halogenation is a process where a halogen (like Br₂) is introduced to an alkane, typically through a radical reaction involving heat or light. This reaction is crucial because alkanes are generally unreactive, and halogenation introduces a functional group that can be further manipulated. For example, once an alkane is halogenated, it can undergo substitution (SN2), elimination, or addition reactions. This initial step is essential for converting simple alkanes into more complex and functionalized organic molecules, making it a foundational technique in organic synthesis.

How does organometal alkylation work in forming carbon-carbon bonds?

Organometal alkylation involves the use of organometallic compounds, which are molecules containing carbon-metal bonds, to form carbon-carbon bonds. A common example is the use of sodium alkynides (R-C≡C^- Na⁺) as strong nucleophiles. These nucleophiles react with electrophiles like alkyl halides (R-X), where the carbon attached to the halogen has a partial positive charge. The nucleophilic carbon attacks the electrophilic carbon, displacing the halogen and forming a new C-C bond. This method is vital for extending carbon chains and constructing complex organic molecules.

What are Zaitsev's and Markovnikov's rules in organic chemistry?

Zaitsev's rule states that during an elimination reaction, the more substituted alkene (the one with more alkyl groups attached to the double-bonded carbons) is usually the major product. This is because more substituted alkenes are generally more stable. Markovnikov's rule, on the other hand, applies to addition reactions and states that the hydrogen atom will add to the carbon with the greater number of hydrogen atoms (the less substituted carbon), while the other part of the adding molecule (like a halogen or hydroxyl group) will add to the more substituted carbon. These rules help predict the outcomes of elimination and addition reactions, respectively.

How can functional groups be moved within a molecule using elimination and addition reactions?

Functional groups can be moved within a molecule by alternating between elimination and addition reactions. First, an elimination reaction is used to form a double bond, which can then be targeted by an addition reaction to introduce a new functional group at a different position. By carefully choosing reagents that follow Zaitsev's or Markovnikov's rules, chemists can control the direction of these reactions. For example, a Zaitsev elimination followed by a Markovnikov addition will move the functional group towards the more substituted part of the molecule. Repeating these steps allows for precise relocation of functional groups.

What reagents are used for Zaitsev and Hoffman eliminations?

Zaitsev eliminations favor the formation of the more substituted alkene and typically use small, strong bases such as NaNH₂, NaH, or alkoxides (RO^-). Hoffman eliminations, which favor the formation of the less substituted alkene, use bulky bases like LDA (lithium diisopropylamide), t-butoxide (KOtBu), or LiTMP (lithium tetramethylpiperidide). The choice of base determines the regioselectivity of the elimination reaction, allowing chemists to control the position of the resulting double bond.