The Competition between Elimination and Substitution

The competition between elimination and substitution channels when an alkyl halide is allowed to react with a nucleophile in the gas phase is a difficult problem to tackle, since in most gas-phase experiments only the ionic products of reaction are monitored (a few exceptions are reported below). Thus, for example, when w-propyl bromide is allowed to react with methoxide ion in the gas phase, the bromide ion produced can arise either by elimination (a) or by substitution (b) and the two pathways cannot be distinguished from the ions alone (Scheme 34). In this specific case it was possible to establish that the reaction follows exclusively the elimination channel through collection and analysis of the neutral products246. The experiments were performed on a FA apparatus configured with a novel cold finger trap coupled to a GC/MS system. Material collected by the trap was separated by capillary gas chromatography and the individual components identified by their retention times and El mass spectra246. 

As we saw in Chapter 8, elimination reactions often compete with nucleophilic substitution reactions. Both reactions can be useful in synthesis if this competition can be controlled. This chapter discusses the two common mechanisms by which elimination reactions occur, the stereochemistry of the reactions, the direction of the elimination, and the factors that control the competition between elimination and substitution. Based on these factors, procedures are presented that can be used to minimize elimination if the substitution product is the desired one or to maximize elimination if the alkene is the desired product. 

The application of Kohn-Sham density functional (DFT) molecular-orbital theory to elementary organic and organometallic reactions has been reviewed. In particular, electronic-structure considerations which provide an understanding of the competition between elimination and substitution reactions (the 2-5n2 mechanistic spectrum) are discussed. 

In the SN1 mechansim, a competition between elimination and substitution also results from the ability of the nucleophile to act as a base. However, in this case the competition occurs at the carbocation stage of the reaction. Figure 8.12 shows an example. Elimination reactions are discussed in more detail in Chapter 9. Chapter 10 presents methods to minimize elimination when the substitution product is desired and methods to maximize elimination when the alkene is the desired product. For now it is important only to recognize that eliminations may decrease the yields in substitution reactions. 

Almost all bases are also nucleophiles, and hence we expect competition between eliminations and substitutions. In both Sn2 and E2 reactions, the nucleophile or base reacts in a single rate-determining step with the reactant. In both SnI and El reactions, the nucleophile or base reacts in a step after the rate-determining heterolysis. Because the experimental observations for substitution and elimination reactions are so similar, we leave the discussion of kinetics to our discussion of substitutions in the next chapter. There are, however, some points that we should make about the factors that influence the extent of 5 2 versus E2 and SmI versus El reactions (Eq. 10.69). 

The adducts themselves are interesting classes of compounds in which the potential for competition between elimination and substitution reactions is being studied. 

In summary, in the competition between SN2 and E2, nucleophiles that are weak bases, minimum steric hindrance, and lower temperatures are used to maximize substitution strong bases, maximum steric hindrance, and higher temperatures are used to maximize elimination. 

A theoretical investigation has been performed by Bickelhaupt et al. [88] on the gas phase reaction of F + Ca/fsF. For this reaction the geometries of the reactants, reactant complexes, transition states, product complexes and the products for anti-E2 and syn-E2 as well as for Sn2 pathways were optimized with the Xa potential [23]. The energetically favoured products FHF + C2-H4 are formed in an anti as well as in a syn E2 mechanism. In their study Bickelhaupt et al. presented a qualitative MO theoretical analysis enabling to understand and to predict which reaction - the elimination E2 or the substitution 5W2 - dominates for a given substrate C2HSL. From their results they concluded that the base plays a key role as a catalyst which strongly influences the competition between syn and anti elimination. Its catalytic effect consists in a considerable stabilization of the transition state. 

Section 8 13 When nucleophilic substitution is used for synthesis the competition between substitution and elimination must be favorable However the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2) Substitution by the Sn2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary Elimination predominates when tertiary alkyl halides react with any anion... 

An El reaction is generally accompanied by a competing SnI reaction, and a mixture of products is generally obtained. At the end of this chapter, we will explore the main factors that affect the competition between substitution and elimination reactions. 

Dehydration and RX formation from alcohols furnish another example of the competition between nucleophilic substitution and elimination. 

Solvolysis of the R,R and R,S isomers of 2-bromo-9-(l-X-ethyl)fluorenes, X = Cl, Br, I, or OBs, in 25% (v/v) acetonitrile in water has been studied with respect to rates of formation of elimination products and of substitution products (X = OH or NHCOMe).142 The parent 9-(l-X-ethyl)fluorenes and the 2,2/-dibromo-9-(l-X-ethyl)-fluorenes were also studied. Various effects of leaving group and of the presence of nucleophiles on the competition between the reactions were observed and the Bronsted equation was applied to the results for the elimination reactions. A related study of solvolysis of 9-(X-methyl)fluorenes, X = I, Br, or Bs, was also carried out, in which the Swain-Scott equation was applied to nucleophilic selectivities in the S 2 reactions.143... 

The competition between nucleophilic substitution and base-induced elimination in the gas phase has been studied using deuterium kinetic isotope effects (KIE).6 The overall reaction rate constants and KIE have been measured for the reactions of RC1 + CIO- (R = Me, Et, t -Pr, and r-Bu). As the extent of substitution in the alkyl chloride increases, the KIE effects become increasingly more normal. These results indicated that the E2 pathway becomes the dominant channel as the alkyl group becomes more sterically hindered. 

S. Gronert, Gas-Phase Studies of the Competition between Substitution and Elimination Reactions, Ace, Chem. Res. 2003, 36, 848-857. 

The number of reactions in this chapter may seem overwhelming at first. The key to success is to remember that nucleophiles react with electrophiles. If you can identify the nucleophile or base and the electrophilic carbon (the one bonded to the leaving group) in each reaction and recall the factors that affect the competition between the two substitution mechanisms and the two elimination mechanisms, the material you have to learn will be much more manageable. 

Elimination reactions are a useful method for the preparation of alkenes, provided that certain limitations are recognized. One problem is the competition between substitution and elimination. The majority of eliminations are done under conditions that favor the E2 mechanism. In these cases, steric hindrance can be used to slow the competing SN2 pathway. Tertiary substrates and most secondary substrates give good yields of the elimination product when treated with strong bases. Sterically hindered bases can be employed with primary substrates to minimize substitution. 

The competition between y9-elimination and substitution reaction determines the proportion of alkene produced. The ratio of elimination to substitution is affected by the solvent as well as other factors (concentration and strength of the attacking base,... 

As we already know (Secs. 5.12 and 8.12), alkyl halides undergo not only substitution but also elimination, a reaction that is important in the synthesis of alkenes. Both elimination and substitution are brought about by basic reagents, and hence there must always be competition between the two reactions. We shall be interested to see how this competition is affected by such factors as the structure of the halide or the particular nucleophilic reagent used. 

Let us return to a problem we encountered before, in the reaction between acetyiides and alkyl halides (Sec. 8.12) competition between substitution and elimination. Both reactions result from attack by the same nucleophilic reagent attack at carbon causes substitution, attack at hydrogen causes elimination. 

Treatment of (silox)3Tam ((32), Scheme 44) with PhNH2 resulted in oxidative addition of an N—H bond to afford the hydride (silox)3Ta(NHPh)(H). This in turn eliminated dihydrogen to form (silox)3Ta(NPh).152 In contrast, the same reaction with p-CF3-C6H4NH2 produced (silox)3-Ta(NH2)(C6H4-p-CF3) from oxidative addition of a C—N bond (Scheme 44).15 The competition between N-H and C-N activation was investigated for a variety of substituted anilines, with electron-withdrawing substituents found to favor C-N activation. 

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