The Zaitsev Rule

Recall from Section 8.1 that a mixture of alkenes can form from the dehydrohalogenation of alkyl halides having two or more different p carbon atoms. When this occurs, one of the products usually predominates. The major product is the more stable product—the one with the more substituted double bond. For example, elimination of the elanents of H and I from 

Quinine, a natural product isolated from the bark of the cinchona tree native to the Andes Mountains, is a powerful antipyretic—that is, it reduces fever—and for centuries, it was the oniy effective treatment for maiaria. 

Bonds and atoms in quinine and estradiol that originate in the alkene intermediate are shown in red. 

This starting materiai has two different P carbons, iabeied p. and P2. 

This phenomenon is called the Zaitsev rule (also called the Saytzeff rule, depending on the translation) for the Russian chemist who first noted this trend. 

More substituted halides react fastest Rate R3CX R2CHX RCHjX Favored by strong bsises Better leaving group — faster reaction Favored by polar aprotic solvents 

Probl6m 8.11 How does each of the following changes affect the rate of an E2 reaction  

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The regioselectivity of dehydrohalogenation of alkyl halides follows the Zaitsev rule p elimination predominates m the direction that leads to the more highly substi tuted alkene... 

Dehydrohalogenation of alkyl halides (Sections 5 14-5 16) Strong bases cause a proton and a halide to be lost from adjacent carbons of an alkyl halide to yield an alkene Regioselectivity is in accord with the Zaitsev rule The order of halide reactivity is I > Br > Cl > F A concerted E2 reaction pathway is followed carbocations are not involved and rearrangements do not occur An anti coplanar arrangement of the proton being removed and the halide being lost characterizes the transition state... 

The least sterically hindered p hydrogen is removed by the base m Hofmann elim matron reactions Methyl groups are deprotonated m preference to methylene groups and methylene groups are deprotonated m preference to methmes The regioselectivity of Hofmann elimination is opposite to that predicted by the Zaitsev rule (Section 5 10) Elimination reactions of alkyltrimethylammonmm hydroxides are said to obey the Hofmann rule, they yield the less substituted alkene... 

With a regioselectivity opposite to that of the Zaitsev rule the Hofmann ehmma tion IS sometimes used in synthesis to prepare alkenes not accessible by dehydrohalo genation of alkyl halides This application decreased in importance once the Wittig reac tion (Section 17 12) became established as a synthetic method Similarly most of the analytical applications of Hofmann elimination have been replaced by spectroscopic methods... 

Quaternary ammonium hydroxides un dergo elimination on being heated It is an anti elimination of the E2 type The regioselectivity of the Hofmann elimina tion IS opposite to that of the Zaitsev rule and leads to the less highly substi tuted alkene... 

When tertiary halides are treated with base, they undergo E2 elimination. The regioselectivity of elimination of tertiary halides follows the Zaitsev rule. 

Acid-catalyzed dehydration yields the more highly substituted alkene, the desired product, in accordance with the Zaitsev rule. 

Formation of the Hofmann Product Bulky bases can also accomplish dehydrohalo-genations that do not follow the Zaitsev rule. Steric hindrance often prevents a bulky base from abstracting the proton that leads to the most highly substituted alkene. In these cases, it abstracts a less hindered proton, often the one that leads to formation of the least highly substituted product, called the Hofmann product. The following reaction gives mostly the Zaitsev product with the relatively unhindered ethoxide ion, but mostly the Hofmann product with the bulky tert-butoxide ion. 

The Zaitsev rule The major product in 3 elimination has the more substituted double bond. 

The alkyl halide has two different p C atoms (labeled Pi and P2), so two different alkenes are possible one formed by removal of HCI across the a and Pi carbons, and one formed by removal of HCI across the a and P2 carbons. Using the Zaitsev rule, the major product should be A, because it has the more substituted double bond. 

Problem 8.12 What alkenes are formed from each alkyl halide by an E2 reaction Use the Zaitsev rule to predict the major product. 

The Zaitsev rule applies to El reactions, too. For example, El elimination of HBr from 1-bromo-1-methylcyclopentane yields alkenes A and B. A, having the more substituted double bond, is the major product. 

Because conformation B has two different axial p H atoms, labeled Hg and Ht, E2 reaction occurs in two different directions to afford two alkenes. The major product contains the more stable trisubstituted double bond, as predicted by the Zaitsev rule. 

Because conformation D has only one axial P H, E2 reaction occurs in only one direction to afford a single product, having the disubstituted double bond. This is not predicted by the Zaitsev rule. E2 reaction requires H and Cl to be trans and diaxial, and with the trans isomer, this is possible only when the less stable alkene is formed as product. 

Draw all constitutional isomers formed in each E2 reaction and predict the major product using the Zaitsev rule. Cl... 

When an alcohol has two or three different P carbons, dehydration is regioselective and follows the Zaitsev rule. The more substituted alkene is the major product when a mixture of constitutional isomers is possible. For example, elimination of H and OH from 2-methyl-2-butanol yields two constitutional isomers the trisubstituted alkene A as major product and the disubstituted alkene B as minor product. 

This regioselectivity distinguishes a Hofmann elimination from other E2 eliminations, which form the more substituted double bond by the Zaitsev rule (Section 8.5). This result is sometimes explained by the size of the leaving group, N(CH3)3. In a Hofmann elimination, the base removes a proton from the less substituted, more accessible carbon atom, because the bulky leaving group on the nearby a carbon. 

Figure 25.11 contrasts the products formed by E2 elimination reactions using an alkyl halide and an amine as starting materials. Treatment of the alkyl halide (2-bromopentane) with base forms the more substituted alkene as the major product, following the Zaitsev rule. In contrast, the three-step Hofmann sequence of an amine (2-pentanamine) forms the less substituted alkene as major product. 

The Zaitsev rule is used to predict the product of elimination when more than one product is possible. According to the Zaitsev rule, the most stable alkene is formed predominantly this is the one in which the double bond is most highly substituted with alkyl groups. 

PROBLEM 5.13 Each of the following alcohols has been subjected to acid-catalyzed dehydration and yields a mixture of two isomeric alkenes. Identify the two alkenes In each case, and predict which one is the major product on the basis of the Zaitsev rule. 

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