Nucleophilic substitution element effects

It should be pointed out that the existence of stable structures of the intermediate-complex type (also known as a-complexes or Wheland complexes) is not of itself evidence for their being obligate intermediates in aromatic nucleophilic substitution. The lack of an element effect is suggested, but not established as in benzene derivatives (see Sections I,D,2 and II, D). The activated order of halogen reactivity F > Cl Br I has been observed in quantita-tivei36a,i37 Tables II, VII-XIII) and in many qualitative studies (see Section II, D). The reverse sequence applies to some less-activated compounds such as 3-halopyridines, but not in general.Bimolecular kinetics has been established by Chapman and others (Sections III, A and IV, A) for various reactions. 

The different C— Le bond strengths arising from the reacting carbon being bound to different elements have a rather small effect on the rate of nucleophilic substitution of substituted benzenes. 

Rappoport and co-workers work has continued in a study of the substitution of ( )-and (Z)-/3-bromo- or chloro-styrenes, (1) and (2), by MeS in DMSO-d 6 (sometimes in admixture with CD3OD) as solvent. Product studies indicated retention stereochemistry rate measurements found only a small Br/Cl element effect, slower reactions of the p-OMe bromo compounds, and retardation by CD3OD. These results are consistent with Tiecco s suggestion in 1983 that even this system, activated by only a single phenyl group, reacts through the nucleophilic addition-elimination multistep route. 

Routes (i) and (ii) differ only in the life-time of the intermediate, although the intermediate of route (i) might only be a transition state. We will see that the stereochemistry of the product and the element effect can give information on this question. Most of the evidence points to a short-lived carbanionic intermediate, but in some examples an a,j8-adduct seems essential. Since even the direct substitution is in itself an addition-elimination process involving the nucleophile and the leaving group, and since differentiation between the routes of Scheme 2 is not always possible, we will designate all routes of Scheme 2 as addition-elimination . 

Table 25. Element effects in nucleophilic substitution reactions of haloalkynes and other halides... 

The answer came from Joseph Bunnett (p. 478), who is responsible for much of what wc understand about nucleophilic aromatic substitution. It was while studying this reaction that he first conceived the idea of element effect (Sec. f4.20), and showed how it gave evidence for the two-step mechanism. 

This review deals with the replacement of substituents in the vinylic position hy anionic or neutral nucleophiles. Its division according to mechanistic routes suffers from the fact that for many systems there is a strong connection and mutual intercalation between several routes, but we will try to show the similarities in the behaviour of different systems and to discuss the various criteria which have been used for differentiation between the mechanistic pathways. Some topics, e.g. the stereochemistry and the element effect, are discussed in greater detail than others, especially when the data could be collected in convenient tables. No attempt has been made to cover all the synthetically used vinylic substitution reactions of which reviews are available, e.g. on /3-chloro-vinyl ketones (Kochetkov, 1952, 1961 Kochetkov et al., 1961 Pohland and Benson, 1966), fluoro-olefins (Chambers and Mobbs, 1965) or tetracyanoethylene (Cairns et al., 1958 Cairns and McKusick, 1961). 

The ratio ki/k is therefore the element effect k jkY of the preceding section for the pair R R =CXY and R R C=CY2, and 2/ 3 is krlkx for the pair R R C=CXY and R R C=CX2. For good carbon nucleophiles, the value in parentheses is expected to be close to unity, as discussed above, i.e. kijkz kijk. Owing to lack of experimental data this analysis has not yet been applied. It would be of interest to compare, for example, the substitution rates of R R =CCl2 and R R C=CF2 and to evaluate in what cases chloride would leave preferentially to fluoride from R R C=CFC1 systems. 

Obtaining both an isotope effect, k /k, and an element effect, k fk, are the experimental evidence that the C-H and C-X bonds are breaking in the transition structure. Since measurement of heavy atom isotope effects requires special instrumentation, the element effect has taken the place of heavy atom isotope effects in most investigations. The element effect was first proposed by Bunnett in a 1957 paper dealing with the nucleophilic substitution reactions of activated aromatic compounds [27], and later applied to dehydrohalogenation mechanisms by Bartsch and Burmett [28]. The lack of any incorporation of deuterium prior to elimination has also been used as experimental evidence favoring the concerted mechanism [29]. The stereochemistry should be a trans-elimination. 

First, the process may not involve a nucleophilic attack on the vinylic carbon. This fact is well recognized in vinylic substitution (2, 3), and a typical example is the substitution of ( )- and (Z)-(3-halovinyl sulfones (3 and 4 X = Cl or Br) by PhS- and MeO- in MeOH (4-6). Both reactions of both substrates are of a second order and give retention of configuration, and the element effects kBJka are 2.3 (E) and 2.2 (Z) with PhS- and 0.84 (E) with MeO-, values that are consistent with rate-determining nucleophilic attack on the vinylic carbon (2). However, for the Z isomer, kBJka with MeO- is 185, and because a-hydrogen exchange is rapid under the substitution conditions, the reaction of the Z-bromide probably proceeds via elimina-... 

Only one or/Ao-aryne 533 is possible in a thiazole ring. Its intermediacy was first considered in the reaction of 4>halothiazoles (534) with methoxide ion as a possible rationale for the surprisingly similar reactivity of these compounds and the 2- and 5-halo isomers. This hypothesis was consistent with the small element effect, the rapid base-catalyzed exchange of the 5-proton, and the exclusive formation of the normal substitution product 535 as would be expected if nucleophilic addition to the aryne 533 was determined by the stability of the resulting anion 536 with the negative charge adjacent to the sulfur atom. The fact that the 5-phenyl derivative 537, which cannot form an aryne 533, reacts at a comparable rate to 534 rules out the possibility of an elimination-addition mechanism, however. 

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