Hey everyone. In this video, I'm going to teach you guys the three rules of nucleophilic acyl substitution. When you go ahead and start studying this section on your own, with the textbook or with the professor's slides, what you're going to find is that there's a ton of reactions in this section. It's like an overabundance. You're going to see acid chlorides turning into esters and esters turning into anhydrides and anhydrides turning into acid chlorides. It's a mess. It can seem really overwhelming. But it turns out that there are three very simple rules that capture almost all of these reactions. If we can just learn these three patterns, it saves you tons of time with memorizing because ideally in this section, you aren't memorizing at all. You're simply predicting and understanding. Here are the three rules. Let's start off with rule number one which is that you need to know your general conversion. Your general NaS conversion says that you can take any carboxylic acid derivative, any derivative and you can turn it into either an anhydride, an ester, or an amide. How do you do that? With the following reagents. For an anhydride, you can use a carboxylate, that just means \( O^- R \). You can use a carboxylate. For an ester, you can use alcohol. And for an amide, you can use amines. That's really it. It just says that you can pretty much take any carbonyl compound that's a carboxylic acid derivative and turn it into one of these three compounds using one of these reagents. Just so you know, there's extra complexity on top of that but this is the basics. You just need to know these three reagents. Let's move on to rule number two.
Rule number two states that more reactive acyl compounds can be easily converted into less reactive ones. How do you know which one is more reactive and which one is less reactive? You look at the strength of the leaving group. The leaving group ability is what tells you which acyl compounds are more reactive and which ones are less. Remember that we talked about what is a \( Z \) group. All those \( Z \) groups have a ranking of their ability to leave. The highest obviously being \( Cl \) because, guys, we've always known that halogens are excellent leaving groups. We've been forming \( X^- \) anions forever now. \( Cl^- \), perfect. It's a great leaving group. As you go down this trend, they get worse and worse. A carboxylate, which is a negatively charged \( O \), so you would think a negatively charged \( O \) would be a really bad leaving group, but remember that it's resonance-stabilized, so it looks something like this: it's not terrible because that negative charge can resonate throughout the oxygens. It actually isn't such a terrible leaver. It's not as good as \( Cl \) but it's not the worst ever. \( OR \) and \( OH \) are about the same. These are actually supposed to be ranking. I'm supposed to be drawing that they're getting worse as we go down this direction. \( OH \) basically hydroxide or oxide, these are worse than a carboxylate because this is going to be a localized negative charge on an \( O \). Now you might be wondering, Johnny, I don't remember \( OH \) being a good leaving group. \( OH \) is actually a pretty bad leaving group because it makes hydroxide which is a base. Yes. But consider that it's still a lot better than an \( R^- \). \( R^- \) like carbon, that would be terrible. We can use base catalyzed or acid catalyzed reactions to make it more favorable. Just keep that in mind. The worst that actually still counts as nucleophilic acyl substitution is \( NHU^- \). \( NHU^- \) is the worst leaving group of this category. That means that what's the order of our carboxylic acid derivatives in terms of reactivity? That means that acid chlorides are the most reactive followed by anhydrides. Esters and carboxylic acids are about tied, and then amides are the worst. According to rule number two, rule number two says that I can turn any more reactive one into a less reactive one easily by just doing a conversion. When we want to do a reaction, we combine rules one and two. If I want to turn an acid chloride into an ester, I would ask myself, is that favored energy-wise? In terms of the reactivity, is that favored to go from acid chloride to ester? Yes, because you can always go to the left. You can always go to the left on this chart. What you can't do is you can't go to the right. That's a difficult direction. Then I would look at the reagent according to rule number one and I would say, why do you need an alcohol to do that? And that would actually work. If you just put those two pieces of information together, you can make up your own reaction on the spot just predicting it based on these two things. One more thing. I didn't talk about that line. What's up over here? Notice that I have \( R \) and \( H \). What do you guys think about these leaving groups? Are carbon leaving groups? Are hydrogen leaving groups good to participate in nucleophilic acyl substitution because you can't kick them out for anything. It turns out that \( R \) and \( H \) is on a completely different spectrum. This is what we call nucleophilic addition because it can't substitute. \( R \)'s and \( H \)'s, you're not going to do an NAS reaction. But for all of these guys here, all of these guys can participate in NAS to varying degrees. Obviously, acid chloride being the best at it and amides being the worst at it. Now we know rule number two. What's rule number three?
Rule number three is the carboxylic acid conversions. Rule number three goes back to the definition of what a carboxylic acid derivative is. What did I tell you guys? I told you that any carboxylic acid derivative, by definition, if
