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7.7b Exceptions to Zaitsev's Rule for E2 Reactions

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So now we've got to talk about some exceptions to Zaitsev's rule. There's really four main ones, but two that are definitely more important than the other two. And the first one is one of the more important ones. And that's involving a bulky base along with a bulky substrate, typically a bulky alkyl halide. So, you notice, in this example I've got a tertiary halide. So, and it turns out this guy right here is what we call a bulky base. This is potassium t-butoxide or potassium tert-butoxide and he is by far the most common bulky base you're probably likely to encounter. So, and if you take a look here- So we've got our alpha carbon right here. Being tertiary. Being tertiary, you've got three adjacent beta carbons here. So one there, one there, one there. These are both secondary. This one's only primary. And so, Mr. Zaitsev's would say "Use one of the secondaries." And it turns out they're both equivalent. So if we use a normal non bulky base, like sodium methoxide here, you'll find that your Zaitsev product, using one of those secondary beta carbons, is the major product. And your Hoffmann, using that primary beta carbon on the outskirts of the molecule there, is the minor product. But if you use your bulky base in this case, due to his bulkiness here, he's going to prefer using the least substituted beta carbon. The primary one in this case. And that's why your major product forms the least substituted alkene. So whereas your minor product is now the Zaitsev. So here, your Hoffmann ends up being the major product with a bulky base. So, and the key here is its a bulky base and a bulky alkyl halide. So the truth is that, its tertiary halides specifically, that are going to always form the Hofmann product as the major product. It turns out it's a kinetic product rather than a thermodynamic product just due to sterics here. But it turns out with a secondary halide, it's not quite so straightforward. Some of the bulkier secondary halides will still form the Hoffmann as the major. Some of the less hindered ones actually might still form the Zaitsev. And so oftentimes what we do here is we just oversimplify the process. And it gets oversimplified in one of two ways, and you want to find out which one your professor is over- simplifying with. Usually we'll just say that "With a bulky base you always get the Hoffmann as the major and the Zaitsev as the minor." That's one way to oversimplify this. The other way would be to say "With tertiary halides, you get the Hoffmann as the major. And with secondary halides you still get the Zaitsev as the major" And again even that's still a little bit of an oversimplification. So, just kind of pay a close attention to which method or which oversimplification your professor is using, because usually it's one or the other. The first is much more likely. So a lot of times, the general rule people just give is that, you know, bulky bases: Hoffman as the major, Zaitsev as the minor. Done. So, again it's really more complicated than that, but oftentimes we just kind of simplify it to that. So we've seen that with a bulky base you often get the Hoffmann product as your major product, rather than is Zaitsev. So I want to show you the most common bulky bases. And we've already talked about the most common by far and that's potassium tert-butoxide here. You might see it represented with the Lewis structure. You might see the condensed formula. Or you might just see it written out in words; either potassium tert-butoxide or potassium t-butoxide. But hands-down the most common bulky base we'll ever use. The other two though that you might see are maybe, DBU and DBN here. So, and this nitrogen right here is the basic one. And due to the big bulkiness of the rings, a lot of sterics is involved. And these also tend to give you the Hofmann product as a major product in E2 reactions. We've also got LDA here, and this one's a little less common for this chapter, but you might see this towards the end of O Chem 2 brought up again. But, just to cover my bases here, LDA, lithium diisopropylamide, slight chance you might see it in this chapter. But more likely not one you'll encounter till the end of O Chem 2. So the second exception to Zaitsev's rule occurs when you have a chance of forming a conjugated pi bond. So, and this one, you may or may not see. It's not the most common thing in the world. But it's totally possible. Totally fair game. But if you look here, we've got our alpha carbon right here. He's got the leaving group. We've got two adjacent beta carbons. This one on the right is tertiary. The one on the left is secondary. And Zaitsev would say "Use the tertiary one." And that would get you our alkene over here. And it would be the more substituted alkene. Well it turns out in this case, the more substituted alkene would actually not be the more stable alkene. If we use the secondary beta carbon on the left instead, we would get the pi bond right here. And the key is, is that it is a, what we call, a conjugated system. And it leads to delocalization of the pi electron. So turns out this occurs most commonly when you have a single sigma bond in between pi electrons. Turns out, these will not be separate systems of pi electrons. It's one big giant system in there. There's delocalization of those pi electrons over the entire conjugated system. Now if you have more than one sigma bond in between pi electrons, we say they're isolated. There's no connection. There's no delocalization associated with that. No lowering of the energy at all. And so it turns out, in this example, the most substituted alkene is actually not the more stable one. The conjugated one actually ends up being more stable. So if you've got a chance of forming a conjugated alkene, let that take priority over Zaitsev's rule. Alright. So, third exception to Zaitsev's rule, is if you have a poor leaving group. And specifically in this chapter, that would be fluoride. So chloride, bromide, iodide, are great leaving groups. And iodide is the best. They're all very negligible bases. Being the conjugate base of strong acids. But HF is a weak acid and F- is an actual, legitimate, weak base. It's a much stronger base than either chloride, bromide, or iodide. Now as such, it's not a great leaving group. So turns out when that's the case, the mechanism, I'm going to say, is a little bit sluggish in an E2 reaction. Let's kind of see how this plays out. So I'm going to draw in one of the beta hydrogens here. So we're going to come and deprotonate. So a proton transfer reaction right here. So, and we're about to dump these electrons in to form a pi bond right here and kick off the fluorine. The problem is, is fluorine's like "You want me to leave? I kind of suck at leaving." And so in his hesitation to leave here, these electrons have trouble dumping into this pi bond. Or else we'd violate this carbons octet rule. And so, in the transition state there's actually a buildup of negative charge on this carbon. And it's very carbanion-like, we say, in the transition state. So carbon and stability is the exact opposite of carbocation stability. And again that transition state being carbanion- like, I'd rather have it on the primary beta carbon than on the tertiary beta carbon. And that's what's kind of behind us getting the Hoffmann product. And forming the Hofmann product, we'd have that carbanion-like structure on a primary carbon. In the Zaitsev product, we would have had it on a tertiary carbon instead. So that's kind of the deal here again. This is a kinetic product. It's not the thermodynamic product. It's not the more stable product. But it does have the lower activation energy, so it's the kinetic product. You may or may not encounter this one. It's the least common of the four exceptions. So if it doesn't look familiar, a good chance it wasn't presented in your course. All right. So here's our fourth exception to Zaitsev's rule and it's not going to make much sense yet. But if you don't have an anti-periplanar hydrogen on your beta carbon, then you can't form an alkene there. So this is going to be a little bit strange here. We'll talk about what anti-periplanar means here in a little bit. But the most common place that it shows up is on cyclohexane. So, in this case, here's our alpha carbon. So, and we've got a beta carbon right here, and a beta carbon right here. And if we draw the relevant hydrogens in. So, here we've got one on a wedge. So and, on the beta one here, we've got one on a wedge and one on a dash. So in this case, on a cyclohexane ring, what ultimately peri- planer is going to need to mean, is that the hydrogen I take from the beta carbon has to be trans to the leaving group. So here's our leaving group. It's on a wedge. So the hydrogen we take has to be on a dash. Trans, on your cyclohexane ring. And these two wedge hydrogens will not work, it turns out. So there's some stereospecificity of sorts with the E2 that we haven't discussed yet. But suffice to say, I just want to point out in this case, this is your other exception to Zaitsev's rule. In this case, we would not be able to use that hydrogen at all and we would not be able to form the alkene in that location. So it turns out we only get it with the other beta hydrogen. This anti-periplanar arrangement here is absolutely mandatory. And we're to take a much deeper look at what it means to be anti-periplanar here. But that's your fourth exception. So, bulky base, bulky substrate, and then this anti-periplanar hydrogen. These are the two most common examples of when you might violate Zaitsev's rule.

Zaitsev's Rule (or Saytzeff's Rule)

Zaitsev's Rule (also spelled Saytzeff's Rule) is used to distinguish the major elimination product(s) when more than one are possible. The elimination reactions we will specifically consider here are dehydrohalogenations resulting in an alkene. Dehydrohalogenation involves losing a hydrogen and a halogen from adjacent carbon atoms (usually) in a molecule while forming a pi bond. The carbon atom bonded to the halogen is referred to as the alpha carbon. All adjacent carbon atoms are referred to as beta carbons and the attached hydrogen atoms as beta hydrogens.

Zaitsev's Rule states that when there is more than one possible beta carbon that can be deprotonated while performing an elimination reaction, the more substituted one (the one with fewer hydrogen atoms attached) is preferred. Deprotonating the more substituted beta carbon will lead to a more substituted alkene. And a more substituted alkene is a more stable alkene...this is ultimately the reasoning behind Zaitsev's Rule. Take for instance the alkyl halide below:

There are three beta carbons: two are secondary carbons and are equivalent and the third is a primary carbon. Zaitsev's Rule predicts that the alkene formed when deprotonating either of the secondary carbons will be the major product (referred to as the Zaitsev product) whereas the alkene formed when deprotonating the primary carbon will be a minor product (referred to as the anti-Zaitsev or Hofmann product) as is the case in the E2 Elimination reaction below:

Zaitsev's Rule Exceptions

While both E1 and E2 Elimination reactions generally follow Zaitsev's rule, there are four notable exceptions for E2 reactions:

1. Using a Bulky Base

2. No antiperiplanar beta hydrogen on cyclohexane

3. Poor Leaving Group

4. Conjugation

1. Using a Bulky Base (with a Bulky Halide)

The majority of undergraduate organic chemistry courses are presented the idea that the use of a bulky base always leads to the anti-Zaitsev (Hofmann) product as the major product. While this is the case with a bulky halide there are examples of some secondary halides still leading to the Zaitsev product as the major product. It is for these exceptions that I qualified the title of this section to include "(with a Bulky Halide)." But the majority of students reading this will not be required to be aware of these exceptions and should just remember the simplified mantra that the use of a bulky base always leads to the anti-Zaitsev product as the major product.

While there are several bulky bases that are used in E2 reactions in practice, the most common by far is t-butoxide. For many classes, this is the only bulky base they are presented with and I show three ways it is often represented below:

Below we can see the difference in the major product in the E2 elimination reaction when a tertiary halide is treated with NaOCH₃ (typical strong base) vs t-butoxide (bulky base).

The Zaitsev product is the more stable product and is therefore the Thermodynamic Product of this reaction (a term you may learn later). Due to the size of t-butoxide, it is considerable 'easier' for it to deprotonate the less substituted beta carbon and therefore the anti-Zaitsev product will form with a lower activation energy. This makes it the faster-forming product and therefore the Kinetic Product (another term you may learn later). So we see that the less substituted alkene is the major product with a bulky base due to steric effects.

I'll conclude this section by showing some of the less common bulky bases.

2. No Antiperiplanar beta Hydrogen on Cyclohexane

The mechanism of an E2 elimination reaction is only possible when the leaving group and a beta hydrogen are antiperiplanar (~180^o apart). For a cycloalkane rotation around the C-C bonds is restricted limiting when a beta hydrogen may be antiperiplanar to the leaving group. Consider the following reaction:

anti-zaitsev no antiperiplanar beta hydrogen

For this E2 elimination there are two beta carbons having hydrogens: one 3^o and one 2^o. Zaitsev's rule would form the alkene using the 3^o carbon. However, this Zaitsev product is not observed and the anti-Zaitsev product is the major product. This can be best understood by examining the cyclohexane chair conformations.

zaitsev's rule cyclohexane chair conformations antiperiplanar

It turns out that an antiperiplanar relationship between the leaving group and a beta hydrogen is only possible when the leaving group is in an axial position. We can see that in the chair conformation on the left that the Br is in an axial position and the E2 reaction only takes place when the reactant molecule is in this conformation.

As the Br points directly up, an antiperiplanar beta hydrogen will point directly down. We can see that there is such an antiperiplanar hydrogen on the 2^o beta carbon (highlighted in red) but not on the 3^o beta carbon. This explains why the E2 elimination is only possible with the 2^o beta carbon and why the Zaitsev product is not observed. The mechanism is shown below.

3. Poor Leaving Group

The third exception to Zaitsev's occurs when you have a poor leaving group. Many students will not encounter this exception while studying E1 and E2 reactions, but may encounter it later in the course in a chapter on amines, but I include it here to be comprehensive. Amongst the halogens, Cl, Br, and I are all good leaving groups, but F is a poor leaving group due to its greater basicity. Another poor leaving group is an amine. The Hofmann Elimination, which you may encounter much later in an undergraduate course, involves just such a leaving group and is the reason the anti-Zaitsev product is commonly referred to as the Hofmann product. Take for instance the following example involving fluorine as the leaving group.

It turns out the E2 mechanism with a poor leaving group still occurs in a single step. But the poor leaving group leads to a 'delay' of sorts in this step which results in significant build up of negative charge on the beta carbon involved (highlighted in blue in the image below; *other partial charges are omitted for clarity). This beta carbon is carbanion-like and as a less substituted carbanion is more stable, the transition state is more stable when the less substituted beta carbon is used. The resulting lower activation energy explains why the anti-Zaitsev product is the major product with a poor leaving group.

Zaitsev's Rule carbanion like transition state

4. Conjugation

This last exception to Zaitsev's rule is the least common and one the majority of students will not come across. But I include to to be comprehensive. It's due to the fact that conjugation lowers the energy of an alkene. Zaitsev's Rule regarding forming the more substituted alkene is based on the fact the more substituted alkene is typically the more stable alkene. But if the less substituted alkene is conjugated it may in fact be the more stable alkene and the major product as in the following example.

You can recognize that the major product is conjugated as there is only a single sigma bond separating the pi electrons of the alkene from the pi electrons of the benzene ring.

In this reactant there are two beta carbons: one 2^o and one 3^o. Zaitsev's Rule would have predicted using the 3^o carbon to form the major alkene product, but the anti-Zaitsev product is the more stable product due to conjugation. The E2 elimination mechanism for formation of the major product is shown.