Ethers reactivity toward nucleophilic substitution

The highly strained three-membered ring of epoxides makes them much more reactive toward nucleophilic substitution than other ethers. 

The aryl halide must be one that is reactive toward nucleophilic aromatic substitution by the addition-elimination mechanism. p-Fluoronitrobenzene is far more reactive than fluorobenzene. The reaction shown yields p-nitrophenyl phenyl ether in 92% yield. 

Activation of allylic ethers. An allylic ether y to an electron-withdrawing group is activated by forming the Fe(CO)4 complex. On acid treatment ionization occurs to generate the allyl cation (still complexed to iron), which is reactive towards nucleophiles such as silyl enol ethers, malonate ester enolates, etc. The substitution is stereoselective. ... 

As we have said, nucleophilic substitution takes place much more readily at an acyl carbon than at saturated carbon. Thus, toward nucleophilic attack acid chlorides are more reactive than alkyl chlorides, amides are more reactive than amines (RNH2), and esters are more reactive than ethers. 

Phenylseleno- and methylseleno-alkyllithiums usually exhibit a closely related reactivity towards carbonyl compounds whether the reaction is performed in THF or in ether. As expected, the nudeophilicity of such species often decreases by increasing the substitution around the ct anionic center (6 and 8 Scheme 112), but interestingly they are often far more nucleophilic than the corresponding alkyl-lithiums. However, in some rare cases employing particularly hindered reaction partners there is a significant difference of reactivity between phenyl- and methyl-selenoalkyllithiums when the reactions are performed in THF, since the former reagents are much less nucleophilic than the latter (compare 11 and 12 in Scheme 113 and 17a-17f in Scheme 114). As general trends, a-methylselenoalkyllithiums are more nucleophilic in ether than in THF (compare 15 in Scheme 113.17d and 17e in Scheme 114 and 24 in Scheme 116). 

Other measures of nucleophilicity have been proposed. Brauman et al. studied Sn2 reactions in the gas phase and applied Marcus theory to obtain the intrinsic barriers of identity reactions. These quantities were interpreted as intrinsic nucleo-philicities. Streitwieser has shown that the reactivity of anionic nucleophiles toward methyl iodide in dimethylformamide (DMF) is correlated with the overall heat of reaction in the gas phase he concludes that bond strength and electron affinity are the important factors controlling nucleophilicity. The dominant role of the solvent in controlling nucleophilicity was shown by Parker, who found solvent effects on nucleophilic reactivity of many orders of magnitude. For example, most anions are more nucleophilic in DMF than in methanol by factors as large as 10, because they are less effectively shielded by solvation in the aprotic solvent. Liotta et al. have measured rates of substitution by anionic nucleophiles in acetonitrile solution containing a crown ether, which forms an inclusion complex with the cation (K ) of the nucleophile. These rates correlate with gas phase rates of the same nucleophiles, which, in this crown ether-acetonitrile system, are considered to be naked anions. The solvation of anionic nucleophiles is treated in Section 8.3. 

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