E2 Elimination of an Alkyl Halide

The E2 mechanism is followed whenever an alkyl halide— be it primary, secondary, or tertiary—undergoes elimination in the presence of a strong base. 

The regioselectivity of elimination is accommodated in the E2 mechanism by noting that a partial double bond develops at the transition state. Because alkyl groups stabilize double bonds, they also stabilize a partially formed tt bond in the transition state. The more stable alkene therefore requires a lower energy of activation for its formation and predominates in the product mixture because it is formed faster than a less stable one. 

Chapter 5 Structure and Preparation of Alkenes Elimination Reactions 

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FIGURE 5 10 Potential en ergy diagram for concerted E2 elimination of an alkyl halide... 

Here s an example how might we prove that E2 elimination of an alkyl halide gives the more highly substituted alkene (Zaitsev s rule, Section 11.7) Does reaction of 1-chloro-l-methylcyclohexane with strong base lead predominantly to 1-methyl cyclohexene or to methylenecyclohexane ... 

Another method of seeking evidence of the EIcBirr mechanism is to exam heavy-atom isotope effects in the leaving group. Of course, these should be much more significant in an E2 process because the bond is breaking in the transition state. For example, Thibblin and co-workersfound that in the base-induced elimination of an alkyl halide in which the p-carbon is unusually acidic (indene derivative, 12), moderately strong bases (triethylamine and methoxide) lead to a significant Cl/ Cl isotope effect = 1.010 1.009, where a maximum effect of... 

All the elimination reactions listed in Review Table 2 occur by the same E2 mechanism. Though they appear different, the elimination of an alkyl halide to yield an alkene (reaction 1), the elimination of a vinylic halide to yield an alkyne (reaction 2), and the elimination of an aryl halide to yield a benzyne (reaction 3) are ail E2 reactions,... 

In fact, the reaction of alkoxides with alkyl halides or alkyl sulfates is an important general method for the preparation of ethers, and is known as the Williamson synthesis. Complications can occur because the increase of nucleo-philicity associated with the conversion of an alcohol to an alkoxide ion always is accompanied by an even greater increase in eliminating power by the E2 mechanism. The reaction of an alkyl halide with alkoxide then may be one of elimination rather than substitution, depending on the temperature, the structure of the halide, and the alkoxide (Section 8-8). For example, if we wish to prepare isopropyl methyl ether, better yields would be obtained if we were to... 

This reaction, called the Hofmann elimination, is quite analogous to the dehydro-halogenaYion of an alkyl halide (Sec. 14.18). Most commonly, reaction is E2 hydroxide ion abstracts a proton from carbon a molecule of tertiary amine is expelled, and the double bond is generated. Bases other than hydroxide ion can be used. 

Because the overall transformation is an elimination reaction, with loss of H and Br, the symbol E, for elimination, is used. It is a bimolecular elimination reaction, so the symbol 2 is used. The elimination reaction of an alkyl halide with a base is known as an E2 reaction. The conversion of 3 to 5 is an example of an E2 reaction, and 4 is a typical E2 transition state. A generalized E2 transition state is drawn as 6, where a base reacts with the -hydrogen and a leaving group X is lost to form the new n-bond. 

Sections 12.1 and 12.2 described the E2 reaction of acyclic alkyl halides. Elimination also occurs with cyclic halides, but the conformational demands of the ring must be taken into account (see Chapter 8, Section 8.5). The E2 reaction must proceed by an anti transition state, which imposes additional conformational demands on ring compounds. 

Ethers are frequently prepared via the Williamson ether synthesis, which involves the reaction of an alkyl halide electrophile (RX) with an alkoxide nucleophile (R O ). As usual, the Sn2 backside attack is sensitive to sterics, and the E2 elimination reaction is expected to compete here since alkoxides are strong bases. The Sn2 substitution can be expected to give good yields of the ether if the halide is on a methyl, primary, allylic, or benzylic carbon. Simple alkoxides may be commercially available otherwise, the alkoxide can be prepared from the corresponding alcohol by treatment with a strong base (NaH) or a metal (Na or K). 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

In each of the following cases draw the structure of an alkyl halide that will undergo an E2 elimination to yield on/y the indicated alkene. 

Like alcohol dehydrations El reactions of alkyl halides can be accompanied by carbocation rearrangements Eliminations by the E2 mechanism on the other hand nor mally proceed without rearrangement Consequently if one wishes to prepare an alkene from an alkyl halide conditions favorable to E2 elimination should be chosen In prac tice this simply means carrying out the reaction m the presence of a strong base... 

The removal of a molecule of a hydrogen halide from an alkyl halide to yield an alkene is effected under strongly basic conditions, e.g. a concentrated alcoholic solution of sodium or potassium hydroxide or alkoxide. This overall reaction has been submitted to most rigorous mechanistic studies. Most of the factors (temperature, nature of base, structure of substrate, solvent, etc.) which control product composition have been evaluated. It thus appears that under the conditions noted above, an E2 process, in which the participating sites adopt an ann -periplanar conformation leading to an anti-elimination process, is generally favoured. 

Table 4.1 gives the chemoselectivity of E2 eliminations from representative bromides of the type Rprim—Br, Rsec—Br, and Rten—Br. The fraction of E2 product increases in this sequence from 1 to 79 and to 100% and allows for the following generalization E2 eliminations with sterically unhindered bases can be carried out chemoselectively (i.e., without a competing SN2 reaction) only starting from tertiary alkyl halides and sulfonates. To obtain an E2 product from primary alkyl halides and sulfonates at all or to obtain an E2 product from secondary alkyl halides and sulfonates exclusively, one must change the base (see Section 4.4.2). 

Dehydrohalogenation is the elimination of a hydrogen and a halogen from an alkyl halide to form an alkene. In Sections 6-17 through 6-21 we saw how dehydrohalogenation can take place by the El and E2 mechanisms. The second-order elimination (E2) is usually better for synthetic purposes because the El has more competing reactions. 

Tlie elimination of HX from an alkyl halide is an excellent method for preparing an utkenc, but the subject is complex because elimination reao tions con take place- through different meeStanistic pathways, just as srub stitutinns can. We ll consider two of the moat common pathways the El sod E2 rtaciions. 

Whereas nucleophilic substitution occurs on heating with water, aqueous potassium carbonate, silver oxide or sodium acetate, elimination reactions occur on heating an alkyl halide with ethanolic potassium hydroxide. Both unimolecular (El) and bimolecular (E2) pathways occur, the former with tertiary and the latter with primary and secondary halides. The reactions of alkyl halides with oxygen nucleophiles are summarized in Scheme 2.3. 

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. 

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