Leaving Groups and Nucleophiles

At this point, the only leaving group you are really familiar with is alkyl halides. It turns out there are 2 more you should definitely know about. 

Leaving Groups

Concept: The 3 important leaving groups to know. 

Video Transcript

At the beginning of this topic, I made some generalizations about nucleophiles and about leaving groups. If you remember about leaving groups, what I said was that there's a lot of different types, but the most common is alkyl halides. And that's what we've been using this entire topic. Another generalization I made was made was with nucleophiles. When I said that just think that a negatively charged nucleophile is strong and a neutral one is weak. I just said, let's just say that for now.
What I want to do for this topic is go more in-depth on leaving groups and nucleophiles so that we can really understand all the different types of strengths instead of just making generalizations. Let's get started with the leaving groups first.
As I said before, alkyl halides are the most common leaving groups of organic chemistry, so 90% of the time you're just going to see alkyl halides and that's why we've been dealing with them so much because they literally are so ubiquitous. They're everywhere. But it turns out that there's other types of leaving groups as well.
Another really common one being sulfonate esters. Now these don't show up as often as alkyl halides, but they do show up a good amount. What a sulfonate ester is it's a molecule with the general formula SO3R. Now typically we wouldn't – and this is actually the way it looks by the way. The sulfonate ester general structure is that you have your chains. Say this is my chain here. And let's say that this is attached. And it's going to be an O then an S and two O's and then an R.
Now typically would we expect O to be a good leaving group? No. Remember that O is not as electronegative as an alkyl halide. It's actually further this way. So we would expect that O would not be a good leaving group and O negative would suck. But, this molecule is special because it can resonate so much. And I did talk about this earlier when we were talking about leaving groups that we could – once I get a negative charge there, this would be able to resonate and make double bonds and distribute that negative charge everywhere.
So sulfonate esters turn out to be really, really good leaving groups, even better than alkyl halides in some cases because they have so much resonance available, so it's going to stabilize the leaving group just like a conjugate base would be stabilized by the resonance effect. Remember that parallel that I drew between conjugate bases and leaving groups? It's the same thing.
So it turns out that the sulfonate ester, you might just see it drawn as SO3R in which case you need to know what that is. You also might see it drawn OSO2R, same thing. That's just the way it's actually drawn out. There's an O first. You need to be able to recognize that that's a leaving group.
But on top of that, you could see a special type of sulfonate ester. Sulfonate ester is the general category, but there's actually three unique types of sulfonate esters. Those are tosylates, mesylates, and triflates. Now the difference between those three actually just has to do with the R group. So everything else is the same. The S is the same. The O's are the same, everything. The only thing that changes is the identity of the R group. So let's go really quickly into that.
If that R group is just a methyl group, which is this middle situation, that's going to be called a mesylate. A mesyl group or a mesylate once it has the negative charge. And it's abbreviated Ms. So if you see that, you know it's a sulfonate ester. How about if it's a benzene ring with a methyl group on it? If it's a benzene ring with a methyl group that 's going to be called a tosylate and that's abbreviated Ts. And then if it's a C with three F's instead of 3 H's, then that's called a trifyl or triflate once it has the negative charge.
Now I know you guys might be wondering when do I use the word tosyl, when do I use tosylate. The ending -ate just means that there's a negative charge. That's common throughout lots of chemistry. We say instead of – I don't know. In orgo two we use it a lot more, that naming system. It just means that if you have an -ate at the end, it just means you have a negative anion.
So anyway, the whole point here is I don't need you to memorize exactly each sulfonate ester. I don't want you to be able to draw it if I give it to you. But what I do want you to be able to do is recognize that if you see these weird letters like OTs or OMs or whatever, that you're going to know that this is a sulfonate ester, so it's a really good leaving group.
Now I did notice one little error here. This should have been OMs, not OTs, so I'm going to change that. But anyway, you guys get the whole point that basically if you see one of these things, consider it the same as an alkyl halide. If there's an RX, it's the same thing as an OMs or whatever.
So that's the first leaving group that I want to tell you guys about. It's important. Don't pay too much attention to it. Just treat it the same as you would an alkyl halide. So if I see a secondary mesylate, that's the same thing as a secondary iodine or whatever.
The next one that I want to talk about is water. Water is actually a pretty common leaving group that we're going to use in a little bit. We haven't used it yet. But the way that we do it, the way we get water as a leaving group is to protonate alcohol with a strong acid.
So what you'll notice here is I have alcohol. Is alcohol typically a good leaving group? No. Typically, it sucks because once I kick off that O, what I'm going to get is OH- and that's very unstable. That's actually a really strong base. So that's not a good leaving group. But if I can protonate the alcohol first with a strong acid like, for example, sulfuric acid, which is a really common one that's used, then it's going to leave as water.
Let me show you. If the first step is let's say – actually let's use an easier one. Let's just use HCl. If my first step is to expose the alcohol to my strong acid, guess what's going to happen? My alcohol is going to grab the H and it's going to become protonated. Once it's protonated, it looks like this, OH2+. That's not very happy the way it is because it has a formal charge now.
Now guess what can happen in the next step. It can leave all on its own just like an alkyl halide would in a mechanism. And then what you're going to get is you're going to get let's say a carbocation if this is an SN1 reaction or an E1 plus water. Is water a good leaving group? Is it stable? Yeah, it's super stable because it's just neutral.
So see that by protonating my alcohol first, I could turn it from a bad leaving group to actually a really good leaving group.
So now you guys know, overall general idea here. Alkyl halides are the most important. You're going to see them all the time. If you see a sulfonate ester, it's going to be one of these weird letters. Don't worry about it too much, just treat it the same as an alkyl halide. If you see water with a strong acid, treat it the same way as an alkyl halide. The whole point is just that it leaks. That's the end goal. I don't want you guys to get mixed up by all this.
These are really the three main ones that we see. We don't see a whole lot of others. So don't worry about anything else as a leaving group except these three categories. 

1. Alkyl Halides

We’ve been dealing with these the whole lesson, formula –RX. You should be cool with these

2. Sulfonate Esters

These are molecules with the general structure –OSO2R or –SO3R. These are the ultimate leaving groups of organic chemistry. They might look a little weird, but in the end of the day, remember they just leave. NBD. 

3. Water

Also an awesome leaving group, formed after alcohol is protonated with a strong acid.

Nucleophiles and Basicity

Concept: Understanding the difference between basicity and nucleophilicity.  

Video Transcript

Now I want to go into nucleophile because remember that I said we have to define nucleophile more than just saying negative is strong and neutral is weak, so I want to remind you guys of what's the difference between a nucleophile and a base because that actually is going to matter for the section, OK? This section has a lot to do with conceptual questions that once again you could get in this chapter and what a nucleophile is if you remember the had to do with the Lewis definition of acids and bases, OK? So IÕm just going to put here nucleophile is the Lewis definition.... Wow OK Johnny can't spell, LEWIS OK? And what that means is that it's a good electron donator, OK? So remember that basically if you can donate electrons easily that's a good nucleophile, OK? What's a good base? Well base is the Bronsted Lowry definition, OK? Remember what the Bronsted Lowry definition is? That you're a good proton acceptor, OK? Now a lot of times a good electron donator is also going to be a good proton acceptor so a lot of times these things are the same nucleophilicity and basicity have a lot of crossover but there are going to be some instances where one of the things gets better and the other one doesn't or even the other one gets worse, it might get better at donating electrons but worse at pulling off a proton and I'm going to show you guys how. So this is the way we determine the rules, the first rule is actually that generalization that I told you guys earlier which is just that if you have a negative charge that's always going to be stronger nucleophile than neutral so that's what I said basically strong versus weak, OK? So you guys already knew the first rule just form me telling you guys that but there's actually two more rules that you guys need to be aware of, OK? So the second rule is that the bulkier of the substrate, OK? If you have a very bulky nucleophile that's going to make it more basic and less nucleophilic, OK? So what am I saying there? What I'm saying is that if you have a really bulky negatively charged compound let's say, OK? That means that it's going to be worse at donating electrons, why? Because going to a more difficult time approaching electrophiles because now it's going to be so bulky, OK? So it's actually worse at donating electrons but it's actually going to be better at pulling off protons, why? Because protons typically are at the edges of molecules so it's easy for it to access a proton but it's hard for it to donate electrons, does that kind of make sense? This is going to come into play later when we talk about elimination reactions and bases that favor elimination because remember elimination is about the base not the electrophile, it's about pulling off a proton, alright? And then finally this is our last rule that you need to know and then we'll be done with nucleophile which is that basicity and nucleophilicity almost always go in the same direction so as you can see as I go toward less electronegative my basicsim and nucleophiles get stronger, OK? And then also as I go up my periodic table my bases and my nucleophile get stronger that has to do with the size effect, remember that? So basically as you go up you're going to be better at donating electrons because you're smaller so you don't like them as much, OK? That's kind of the point and here I have a little drawing to show that but it turns out that there is going to be an exception to the rule and the exception comes with protic solvents, so as you can see in an aprotic solvent this is what the nucleophile look like, they just look naked, OK? I'm going to put here they're naked, OK? Pretty scandalous, there's nothing around them shielding them or whatever, OK? But then if you have a protic solvent, what did I say about protic solvents? Well protic solvents if you guys need to be reminded are solvent that can hydrogen bond if you can hydrogen bond these are solvents that are typically attracted to charges so they're attracted to positive charges and negative charges so what they're going to do is they're going to do something called solvating, OK? They're going to surround that negative charge so here I've drawn a picture of water which can hydrogen bond its protic solvating fluorine and solvating iodide, fluoride and iodide and we find.....Let me just move out of the way here for a second is that when you have a smaller anion like fluorine or like fluoride the protic molecules are able to surround it better and able to more tightly solvate it so what that means is that it's going to be a worse electron donor because it's so covered up, OK? It's really solvated that's the word for it, OK? Solvated just means it's covered in all these water molecules, OK? Whereas an iodide is so much bigger that it's going to be more loosely solvate, it's going to be more difficult for all the water to cover all the spots it has a lot more surface area so it's actually going to better electron donor even though it's a worse nucleophile, OK? So it turns out that in a protic solvent iodide is actually going to be your best nucleophile, OK? So this trend is reversed as you guys can see in a protic solvent this trend is reversed but in an aprotic solve it the trend is the way it was at the beginning which is just that F is the best nucleophile and I is the worst, OK? So this is going to be the one thing that you guys have to remember in terms of concept because you could get.... I see this kind of question all time and in all kinds of exams all kind of test banks where professors will ask what's the best nucleophile in a protic solvent? What's the worst nucleophile in an aprotic solvent? So you need to have these trends memorized like the back your hand to answer those kinds of conceptual questions, now does it matter so much for mechanisms? Not usually, usually like I said mechanisms aren't determined by the solvents necessarily but you should still know it because it's going to give you a better understanding of the concept of this chapter, alright? So I hope that made sense let me know if I can explain it any better make sure to ask questions this is something that typically a lot of students feels a little bit confusing, I hope that my little drawing here this is actually a new drawing I just made for you guys I hope that it will help you guys kind of relate to what I'm talking about a little better, OK? So let's go ahead and move on to the next topic.

Recall that a Nucleophile is an electron pair donor (Lewis Base), and a Base is a proton acceptor (Bronsted-Lowry Base).

While the terms nucleophile and base often mean the same thing, there are some exceptions where basicity and nucleophilicity do not mirror each other.

Relative Strength Rules:

  1. A negative charge will always be a stronger nucleophile than its neutral counterpart.
  2. The bulkier the base, the more basic and less nucleophilic it is.
  3. Basicity and nucleophilicity have opposite size trends in polar protic solvents. 

Leaving Groups and Nucleophiles Additional Practice Problems

The following is a stepwise synthesis by applying Bronsted‐Lowry (B‐L) and Lewis acid‐base (LA and LB) reactions. Please use electron‐pushing arrows to show this transformation logically.

A. Draw compounds C, D, and F in the boxes.

B. Circle the correct answer(s) clearly and carefully:

Step 1 is:       Bronsted‐Lowry reaction     or     Lewis acid‐base reaction
Step 2 is:       Bronsted‐Lowry reaction     or     Lewis acid‐base reaction
Nucleophile:  A     B     C     D     E     F
Electrophile:  A     B     C     D     E     F
Lewis acid:    A     B     C     D     E     F
Lewis base:   A     B     C     D     E     F

Watch Solution

Create the full arrow pushing mechanism which shows all intermediates and all products that result from these reactions and label minor and major products if they are not equal in potential energy.

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 Provide the major product for the following reaction. 

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Hydroxyl groups can be transformed into tosylate, which is a good leaving group that retains the original stereochemistry. Determine the products in each of the steps of this synthesis reaction. 

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The transformation of the hydroxyl group into a good leaving group can be accomplished through the use of various reagents. 

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When (1R,2S)-1-bromo-2-methylcyclohexane is dissolved in methanol, six possible products are formed. Predict what FOUR (4) of those products should be. 

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All of these reactions, except one, will require some sort of protecting group. (Note that you may not actually know a good protecting group for each reaction.) Which reaction  does not require a protecting group to work (which would work exactly as shown)? Assume and acid quench if needed.

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Can methyl fluorides (e.g., CH3F) undergo substitution? Explain in one sentence.

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Which of the following could be used to synthesize 1-bromopentane?

A) CH3CH2CH2CH=CH2 + HBr →





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For each of the following, supply a structural formula for the  major organic product(s) when the product(s) is(are) not given: if no reaction occurs, write  N.R. 

Provide the following when a product is given. If an organic reactant is missing, supply a structural formula; if an organic reactant (reagent) or catalyst is missing, simply give a formula. Give the best possible answers. Be sure to show stereoisomers properly when necessary.

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Which is the strongest nucleophile?

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