Nucleophilic Substitution: The Three Rules

Concept: Concept: NAS - The Three Rules

10m
Video Transcript

Hey everyone. In this video I'm going to teach you guys the three rules of nucleophilic acyl substitution. So guys, when you go ahead and start studiene this section on your own and 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 acyl, it's a mess, okay? And it can seem really overwhelming but it turns out that there are three very simple rules that capture almost all of these reactions and if we can just learn these three patterns it saves you tons of time with memorizing because ideally in the section you aren't memorizing at all, you're simply predicting and understanding, okay? So, here are the three rules, let's start off with rule number one, which is that you need to know your general conversion. So, your general NAS conversions say that you can take any carboxylic acid derivative any derivative and you can turn it into an either into an anhydride or an ester or an amide, how do you do that with the following reagents. So, for an anhydride you can use a carboxylate, so that just means O negative R. So, you can use a carboxylate, for an ester you can use alcohol, okay? And for an amide you can use amines, okay? So, that's really it, it just says that usually, I mean, that you can pretty much take any carbonyl compound that the carboxylic acid derivative and turn it into one of these three compounds using one of these reagents, okay? Now, just so you know there's extra complexities on top of that but this is the basics. So, you just need to know these three reagents, okay? So, let's move down to rule number two, rule number two states that more reactive acyl compounds can be easily converted into less reactive ones, okay? So, how do you know which one is more reactive and which one is less reactive? Well, 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. So, remember that we talked about what is the z group, all those z groups have a ranking of their ability to leave, the highest obviously being a Cl because guys, we've always known that alkyl groups are, I'm sorry, not alkyl groups, that halogens are excellent leaving groups, okay? We've been forming x negative anions forever now, okay? So, Cl negative, perfect it's a great leaving group, as you go down this trend they get worse and worse. So, a carboxylate would be a little bit worse, okay? Now, it's 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. So, it's not terrible, because that negative charge can resonate throughout the oxygens so it actually isn't such a terrible leaving group, it's not as good as Cl but it's not, you know, the worst ever. Now, OR and OH are about the same, okay? So, these are supposed to be ranking, I'm supposed to be drawing that they're getting worse as we go down this direction. Now, OH basically hydroxide or 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 pretty bad leaving group because it makes hydroxide, which is a base, yes, but consider that it's still a lot better than R negative, R negative carbon, that would be terrible, and we can use base catalyzed or acid catalyzed reactions to make it more favorable, okay? Just keep that in mind, the worst that actually still counts as nucleophilic acyl substitution is NH2 minus, okay? NH2 minus is the worst leaving group of this category, so that means that what's the order of our carboxylic acid derivatives in terms of reactivity? Well, that means that acid chlorides are the most reactive followed by anhydrides, esters and carboxylic acids are both tied and then amides are the worst, okay? So, 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, okay? So, 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, well, is that favored energy-wise in terms of the reactivity is that favored to go from active quarter to Esther? yes, because you can always go to the left, okay? You can always go to the left of the chart, what you can't do is you can't go to the right, that's the difficult direction, okay? And then I would look at the reagent according to rule number one and I would say? Well, you need an alcohol to do that and that would actually work, 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.

Now, guys one more thing, I didn't talk about that line. So, what's up over here. Notice that I have R an H. So, what you guys think about these leaving groups, are carving are hydrogen leaving groups good leaving groups? no guys, these suck, in fact, they suck so bad that they're not even going to participate in nucleophilic acyl substitution because you can't kick them out for anything, so it turns out that R and H is on a completely different spectrum, this is what we call nucleophilic addition, okay? Because it can't substitute. So, 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, okay? So, now we know rule number two, what's rule number three? rule number three is the carboxylic acid conversions, okay? Rule number three goes back to the definition of what a carboxylic acid derivative is, what did I told you guys? I told you that any carboxylic acid derivative by definition if you combine it with water and acid or base, I'm going to remove myself from the screen here, you can turn it into a carboxylic acid, okay? So, that applies to all of these, that means that, for example, put myself back in, amide, right? You got an amide and you react it with water and let's say acid, okay? Now, in terms of energy, does it make sense for the amide to easily become a carboxylic acid? What did I tell you guys about and about favorability? is it's favorable to go to the right or to the left? it's favorable to go to the left, it's unfavorable to go to the right. So, this reaction according to rule number two shouldn't happen because it should be difficult to go from an amide to a carboxylic acid but rule number three is going to trump rule number two because it's its own rule, rule number three says by definition, even if it doesn't make energy-wise an amide should be able to become a carboxylic acid using water and a combination of, you know, acid or base, okay? So, that's where rule number three comes in, that you can always turn any derivative into a carboxylic acid using water or acid. Now, over here, I got the other arrow. Now, these are not reversible arrows, guys they're just separate Direction arrows one on the bottom is z. Now, obviously Z is going to depend on the exact acyl group we're trying to create. So, these are ones that we're going to have to memorize, okay? So, the z groups, we're going to have a separate video for that and I'm going to talk about what reagents would specifically turn carboxylic acid into, you know, whatever you're trying to make. So, those are Z groups but the one that I really want you to focus on for this page is that you can turn any console got the derivative including a nitrile, right? Including a nitrile, into a carboxylic acid using water and hydrolysis, okay? This process is called hydrolysis and this is rule number three. Perfect guys. So, that's it for the three rules, let's move on.

Problem: Determine the major product for the following reaction.

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Problem: Determine the major product for the following reaction. 

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Problem: Determine the major product for the following reaction. 

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Problem: Determine the major product for the following reaction. 

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Nucleophilic Substitution: The Three Rules Additional Practice Problems

Give step by step mechanism for the following transformation:

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Complete the following reaction supplying the missing product and showing correct regio- and stereochemistry where applicable. If a racemic or diastereomeric mixture forms show all stereoisomers; if no reaction takes place, write N.R.

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Arrange the following compounds so that reactivity towards aqueous potassium hydroxide increases from left to right.

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Predict the products and indicate the relative stereochemistry for the following transformations. When necessary indicate the major product.

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Draw the organic product(s) of the following reaction. Indicate stereochemistry where appropriate. A reasonable answer may be “ No Reaction.”

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Draw the organic product(s) for the following reaction. Indicate stereochemistry where appropriate. Assume an aqueous workup, when necessary. A reasonable answer may be “ No Reaction.”

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Consider the formation of an amide from an ester. 

An estimate of the overall enthalpy of this transformation using the bond dissociation energies given below is 

1) 13 kcal/mol     2) – 4 kcal/mol     3) – 17 kcal/mol 4) 7 kcal/mol    5) –11 kcal/mol

Bond dissociation energies (kcal/mol) 

C–H                                      99

C–O                                      79

C–C                                      85

C–N                                      66

R2N–H                                 92

C=O                                    175

C=N                                    145

RO–H                                 109

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Which reaction would not proceed in good yield as written?

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Predict the product(s) in the following reaction. If more than one product is possible, then indicate the major product.

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Draw the major product(s) for the following reaction. Assume the nucleophile is in excess. If there will be no reaction, write NR.

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Determine the necessary reagent and provide the mechanism for the reaction below.

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Rank in order of decreasing reactivity in toward nucleophilic addition-elimination.

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Show the product(s) for the acid catalyzed reaction between formic acid and 1-pentanol. 

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Provide the product for the following reaction. 

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Choose the reaction coordinate that best describes the following reaction.

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Which reaction is the  least favorable (lowest Keq)?

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Predict the product(s) formed in the following reaction.

 

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Predict the product for the following reaction

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Predict the major product for the following reaction, paying attention to the regio- and stereochemistry where appropriate. 

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Predict the major product for the following reaction, paying attention to the regio- and stereochemistry where appropriate. 

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What is the final principal organic product from the following transformation?

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What is the result of treating benzoyl chloride with aniline followed by LiAlH 4 then water?

a) PhNHCH2Ph (Ph = phenyl)

b) Diphenylamine

c) Dibenzylamine

d) N-Phenylbenzamide

e) None of the above

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