7.7b Exceptions to Zaitsev's Rule for E2 Reactions

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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:

zaitsevs rule beta hydrogens

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

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:

potassium t-butoxide

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).

zaitsev vs hofmann 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.

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 (~180o 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 3o and one 2o.  Zaitsev's rule would form the alkene using the 3o 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 2o beta carbon (highlighted in red) but not on the 3o beta carbon.  This explains why the E2 elimination is only possible with the 2o beta carbon and why the Zaitsev product is not observed.  The mechanism is shown below.

zaitsev's rule E2 mechanism

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.

zaitsevs rule poor 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.

Zaitsev's rule conjugation

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.

zaitsev's rule E2 mechanism conjugation

In this reactant there are two beta carbons: one 2o and one 3o.  Zaitsev's Rule would have predicted using the 3o 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.