Structure-Function Correlations with the Nucleophile

The rates of Sn2 reactions correlate well with relative nucleophilicities, because the nucleophile is intimately involved in the rate-determining step. In SnI reactions, the nucleophile is involved after the rate-determining step. Furthermore, the product ratios observed for Sn 1 reactions, when more than one nucleophile is present, do not correlate very well with relative nucleophilicities. This is because reactions with very unstable intermediates, such as carbenium ions, are not selective (see the reactivity-selectivity principle in Chapter 7). They occur at close to diffusion controlled rates. Therefore, in the following discussion, little needs to be said about the influence of the nucleophile on SnI reactions. Instead, our focus is on Sn2 reactions. 

All else being equal, the better the nucleophile, the faster the Sn2 reaction. In Section 8.4.5 we examined a linear free energy relationship for niicleophilicity, called the Swain-Scott equation. The reference reaction for the Swain-Scott measure of nucleophilicities is an Sn2 reaction, that of methyl iodide and methanol. Therefore, the chemical intuition that most chemists rely upon for predicting relative nucleophilicity is actually based upon how the structure of the nucleophile influences Sn2 reactions (Table 8.5). 

Substitution reactions on aliphatic compounds are some of the most prevalent reactions known. Nature needs to perform these reactions, too, but at a rate appropriate for metabolism. Hence, enzymes are involved for many such reactions. As one example, the enzyme haloalkane dehydrogenase from the bacteria Xanthobacter autotrophicus catalyzes the detoxification of 1,2-dichloroethane. Many of the methods of catalysis noted in Chapter 9 are operative with this enzyme, such as proximity of the nucleophile and stabilization of the transition state. 

Below we show a schematic drawing of the catalysis by this enzyme. Covalent catalysis is used, in that the 

A variety of Swain-Scott sensitivity s values for different reactions are given in Table 11.4. These are based upon CH3Br as the standard reactant. We find that the Sn2 reaction of ethyl tosylate is less sensitive to the power of the nucleophile than methyl bromide, as is benzyl chloride. 

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