Nucleophilic substitution versus elimination

Examples of the solvent-dependent competition between nucleophilic substitution and / -elimination reactions [i.e. SnI versus Ei and Sn2 versus E2) have already been given in Section 5.3.1 [cf. Table 5-7). A nice example of a dichotomic y9-elimination reaction, which can proceed via an Ei or E2 mechanism depending on the solvent used, is shown in Eq. (5-140a) cf. also Eqs. (5-20) and (5-21) in Section 5.3.1. The thermolysis of the potassium salt of racemic 2,3-dibromo-l-phenylpropanoic acid (A), prepared by bromine addition to ( )-cinnamic acid, yields, in polar solvents [e.g. water), apart from carbon dioxide and potassium bromide, the ( )-isomer of l-bromo-2-phenylethene, while in solvents with low or intermediate polarity e.g. butanone) it yields the (Z)-isomer [851]. 

Secondary halides are borderline, and substitution or elimination may be favored, depending on the particular base/nucleophile, solvent, and temperature at which the reaction is carried out. Elimination is favored with strong bases/good nucleophiles—for example, hydroxide ion and ethoxide ion. Substitution is favored with weak bases/poor nucleophiles—for example, acetate ion. Table 7.7 summarizes these generalizations about substitution versus elimination reactions of haloalkanes. 

Chapters 11 and 12 discuss reactions of alkyl halides to give either substitution or elimination products. It is clear from Chapter 12 that elimination occurs when the nucleophile is also a strong base and when substitution is inhibited due to steric hindrance. There are many cases in which substitution and elimination compete, particularly when the substrate is a secondary alkyl halide. The solvent plays an important role in these reactions, and solvent identification is a key parameter for distinguishing bimolecular versus unimolecu-lar (ionization) processes. The nature of the alkyl halide (1°, 2°, or 3°) is important, as is the strength of the nucleophile and whether or not that nucleophile can also react a strong base. This chapter will discuss those factors that influence both substitution and elimination, as well as introduce several assumptions that will help make predictions as to the major product. 

For a secondary halide in a reaction with a base, with water as the solvent, ionization is a competitive process. Most of the time, the 8 2 is faster than the Sf fl reaction because direct attack at the a-carbon is more facile than ionization, but the extent of direct substitution versus ionization and then trapping with a nucleophile depend on the strength and nature of the nucleophile. If the nucleophile is a weak base, the Sn2 reaction will dominate in an aprotic solvent. If the nucleophile is a strong base, elimination competes with substitution, and a mixture of Sn2 and E2 products is predicted. In water, it is not obvious whether ionization will lead to the major product, although it is assumed that in aqueous media the 8 1 reaction will dominate. 

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 coupling of allenyl alcohols bearing a hydroxy group in the y- or d-po-sition to the allenyl moiety results in the formation of the cyclic ethers 193 (Scheme 84). Some representative examples are given in Table 39. The reaction mechanism is the same as above. The difference is in facility of the nucleophilic attack versus 0-hydrogen elimination. The presence of a free hydroxyl group in 194 juxtaposed such that either a five or six-membered cyclic ether can form allows nucleophilic substitution to proceed to give 195 (Scheme 85) [122]. 

Effect of Solvent on Elimination versus Substitution. Increasing polarity of solvent favors Sn2 reactions at the expense of E2. In the classical example, alcoholic KOH is used to effect elimination, while the more polar aqueous KOH is used for substitution. Charge-dispersal discussions, similar to those on page 450, only partially explain this. In most solvents, SnI reactions are favored over El. The El reactions compete best in polar solvents that are poor nucleophiles, especially dipolar aprotic solvents" A study made in the gas phase, where there is no solvent, has shown that when 1-bromopropane reacts with MeO only elimination takes place no substitution even with this primary substrate." ... 

Addition of dimethylsulfonium methylide (122) to various Michael acceptors (121), followed by alkylation, has been reported to produce functionalized 1-substituted alkenes (124), arising via the unprecedented elimination (123), rather than the usual cyclopropanation products. In silyl substituted substrates, where a facile Peterson-type olefination is possible from the adduct, elimination took place instead. Aryl-substituted Michael acceptors (121 R1 = Ar) underwent a similar olefination to give 1-substituted styrene derivatives with moderate yields along with a side product, which arose by nucleophilic demethylation from the adduct of dimethylsulfonium methylide and arylidene malonates. Hammett studies revealed that selectivity for olefination versus demethylation increases as the aryl substituent becomes more electron deficient.164... 

We can also rationalize selectivity for elimination versus substitution, or attack of H versus attack on C in terms of hard and soft electrophiles (pp. 237-238). in an Sn2 substitution, the carbon centre is a soft electrophile—it is essentially uncharged, and with leaving groups such as halide the C-X a is a relatively low-energy LUMO. Substitution is therefore favoured by nucleophiles whose... 

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