Alkylation of nitriles
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص585-586
2025-06-25
795
The nitrile group, which mirrors the carbonyl group in general reactivity, is much less easily attacked by nucleophiles (N is less electronegative than O). The anion formed by deprotonating a nitrile using strong base will not react with other molecules of nitrile but will react very efficiently with alkyl halides. The slim, linear structure of the anions makes them good nucleophiles for SN2 reactions.
The nitrile does not have to be deprotonated completely for alkylation: with sodium hydroxide only a small amount of anion is formed. In the example below, such an anion reacts with propyl bromide to give 2-phenylpentanenitrile.
Nitrile-stabilized anions are so nucleophilic that they will react with alkyl halides rather well even when a crowded quaternary centre (a carbon bearing no H atoms) is being formed. In this example the strong base, sodium hydride, was used to deprotonate the branched nitrile completely and benzyl chloride was the electrophile. The greater reactivity of benzylic electrophiles compensates for the poorer leaving group. In DMF, the anion is particularly reactive because it is not solvated.
The compatibility of sodium hydride with electrophiles means that, by adding two equivalents of base, alkylation can be encouraged to occur more than once. This dimethylated acid was required in the synthesis of a potential drug, and it was made in two steps from a nitrile.
Double alkylation with two equivalents of NaH in the presence of excess methyl iodide gave the methylated nitrile, which was hydrolysed to the acid. The monoalkylated product is not isolated—it goes on directly to be deprotonated and react with a second molecule of MeI.
With two nitrile groups, the delocalized anion is so stable that even a weak, neutral amine (triethylamine) is sufficiently basic to deprotonate the starting material. Here double alkyl ation again takes place, in 100% yield: note that the electrophile is good at SN2, and the dipolar aprotic solvent DMSO (like DMF) cannot solvate the ‘enolate’ anion, making it more reactive.
If the electrophile and the nitrile are in the same molecule and the spacing between them is appropriate, then intramolecular alkylation entails cyclization to form rings. The preparation of a cyclopropane is shown using sodium hydroxide as the base and chloride as a leaving group. With an intramolecular alkylation, the base and the electrophile necessarily have to be present together, but the cyclization is so fast that competing SN2 substitution of Cl− by HO− is not a problem.
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