Product Code Database
Although nitrile anions are functionally similar to enolates, the extra multiple bond in nitrile anions provides them with a ketene-like geometry. Additionally, deprotonated can act as masked acyl anions, giving products impossible to access with enolates alone.
Arylacetonitriles (e.g. phenylacetonitrile) are sufficiently acidic to undergo deprotonation with aqueous base, e.g., under phase-transfer catalysis. Nitrile anions can also be involved in Michael reaction-type additions to activated double bonds and vinylation reactions with a limited number of polarized, unhindered acetylene derivatives.
Nitrile anions also arise by conjugate additions to α,β-unsaturated nitriles, reduction, and transmetallation.
The primary difficulty for alkylation reactions employing nitrile anions is over-alkylation. In the alkylation of acetonitrile, for instance, yields of monoalkylated product are low in most cases. Two exceptions are alkylations with (the nearby negative charge of the opened epoxide wards off further alkylation) and alkylations with cyanomethylcopper(I) species. Side reactions may also present a problem; concentrations of the nitrile anion must be high in order to mitigate processes involving self-condensation, such as the Thorpe–Ziegler reaction. Other important side reactions include elimination of the alkyl cyanide product or alkyl halide starting material and amidine formation.
The cyclization of ω-epoxy-1-nitriles provides an interesting example of how stereoelectronic factors may override steric factors in intramolecular substitution reactions. In the cyclization of 1, for instance, only the cyclopropane isomer 2 is observed. This is attributed to better orbital overlap in the SN2 transition state for cyclization. 1,1-disubstituted and tetrasubstituted epoxides also follow this principle.
Conjugated nitriles containing γ hydrogens may be deprotonated at the γ position to give resonance-stabilized anions. These intermediates almost always react with α selectitivity in alkylation reactions, the exception to the rule being anions of ortho-tolyl nitriles.
Formation of cyanohydrins from carbonyl compounds renders the former carbonyl carbon acidic. After protection of the hydroxyl group with an acyl or silyl group, cyanohydrins can function essentially as masked acyl anions. Because ester protecting groups are base labile, mild bases must be employed with ester-protected cyanohydrins. α-(Dialkylamino)nitriles can also be used in this context.
Examples of arylation and acylation reactions are shown below. Although intermolecular arylations using nitrile anions result in modest yields, the intramolecular procedure efficiently gives four-, five-, and six-membered benzo-fused rings.
Acylation can be accomplished using a wide variety of acyl electrophiles, including carbonates, chloroformates, , , and . In these reactions, two equivalents of base are used to drive the reaction towards acylated product—the acylated product is more acidic than the starting material.
Polyanions of nitriles can also be generated by multiple deprotonations, and these species produce polyalkylated products in the presence of alkyl electrophiles.
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