Matching Nucleophiles with Electrophiles

MATCHING NUCLEOPHILES WITH ELECTROPHILES

Having defined nucleophilic and electrophilic carbon species and having learned to produce a variety of them, the next step is to match the reactivities of the nucleophiles and electrophiles so that carbon–carbon bond formation can occur in a controllable and selective fashion. Qualitatively the order of reactivities for nucleophiles and electrophiles used in carbon–carbon bond-forming reactions are shown below. In general, many of the most useful carbon–carbon bond-forming reactions take place with nucleophiles and electrophiles in the middle ranges of reactivity. Highly reactive electrophiles and nucleophiles are often difficult to control while nucleophiles and electrophiles of low reactivity often fail to react effectively. Nevertheless it is reactivity matching that is most important in producing useful reactions.

When stabilized (and consequently less reactive) anions are employed as the nucleophile, more reactive electrophiles are needed for successful carbon–carbon bond formation. Nitronate anions, which are highly resonance stabilized, fail to react with simple alkyl halide electrophiles. On the other hand, β-dicarbonyl compounds react effectively with primary and some secondary alkyl bromides and iodides to give monoalkylated products.

Under the same conditions simple enolates react vigorously with alkyl halides (which must be primary) to give mono- and polyalkylated products. The reactivity of the simple enolate is greater and cannot be controlled at room temperature. However, if the alkylation is carried out at low temperature, the reaction can be controlled and smooth monoalkylation of simple enolates can be achieved. The same is true for the alkylation of acetylide anions, which must be carried out at low temperature for successful alkylation.