Neutral Carbon Nucleophiles

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Chapter: Organic Chemistry : Carbon-Carbon Bond Formation Between Carbon Nucleophiles and Carbon Electrophiles

Other types of carbon nucleophiles such as uncharged enol derivatives and other π -bonded systems are only weakly nucleophilic and consequently unreactive toward normal carbon electrophiles like carbonyl compounds or alkyl halides or sulfonates.


NEUTRAL CARBON NUCLEOPHILES

Other types of carbon nucleophiles such as uncharged enol derivatives and other π -bonded systems are only weakly nucleophilic and consequently unreactive toward normal carbon electrophiles like carbonyl compounds or alkyl halides or sulfonates. For them to be used effectively as nucleophiles, strong electrophiles must be used to match this reduced nucleophilicity. This can be accomplished by increasing the reactivity of a normal electrophile. Typically this is done by treating an electrophile with a Lewis acid. Coordination of lone pairs of electrons with the Lewis acid increases the electrophilicity markedly.

Examples are


A variety of Lewis acids can be used. Among the more commonly used ones are AlCl3, TiCl4, SnCl4, ZnCl2, BF3, and TMSOTf (trimethylsilyl triflate). The choice of Lewis acid is often critical to the success of the reaction and is usually made by referring to similar transformations that have been successfully reported in the literature. Often it is not possible to rationalize why one Lewis acid works and another one does not, so the initial choice of catalyst is normally made by literature precedent. With the arsenal of Lewis acids available a suitable catalyst can usually be found.

By this strategy, reactive carbon electrophiles can be generated for successful reaction with a variety of weak carbon nucleophiles. More important examples include the Friedel–Crafts reaction in which aromatic compounds (nucleophiles) react with alkyl and acyl halides (electrophiles in the presence of Lewis acids).


The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a β-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur.


The transition state is thought to be an open structure. Assuming that a particular silyl enol ether geometry is used, the substituents will tend to occupy opposite faces of the transition state and thus give a particular diastereomer (syn–anti) preferentially. Because of the open transition state geometry, the diastereoselec-tivity is not high.

The reaction of allyl silanes with aldehydes and ketones activated as elec-trophiles by Lewis acids is a very useful method for preparing homoallylic alcohols. Since allyl silanes are only modestly nucleophilic, strong electrophiles are needed to ensure a good reactivity match.


The same considerations apply to intramolecular versions. For example, although epoxide E is a stable compound, treatment with a Lewis acid activates the epoxide as an electrophile and cyclization with the olefinic π system occurs to give the steroid ring system. Note that the silyl enol ether group of E functions as the terminating group. This polyene cyclization is similar to the way in which steroids are biosynthesized. The cyclization is triggered by the generation of an electrophile sufficiently strong to react intramolecularly with the weakly nucleophilic π bond.


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