Grignard reagents with nitriles

Kctonescan be prepared by the reaction of Grignard reagents with nitriles. The initial product is a ketimine, which does not react further with the Grignard reagent, thereby preventing formation of the tertiary alcohol. Subsequent hydrolysis gives the ketone (Scheme 10.8). 

Reactions of either Grignard or organolithium reagents with most aldehydes, ketones, or esters produce alcohols. Reactions of organolithium reagents with carboxylic acids, or of Grignard reagents with nitriles, produce ketones. 

Much improved yields of ketones, formed by reaction of Grignard reagents with nitriles 33, have been obtained when reactions were performed in benzene containing 1 Eq of diethyl ether, rather than in diethyl ether alone [51]. Under the modified conditions, it is postulated that reaction occurs through a species in which the nitrile has displaced a diethyl ether solvent molecule from a dimeric Grignard species. 

FIGURE 14.62 Mechanism of reaction of Grignard reagents with nitriles. 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

The reactions of Grignard reagents with aldehydes and ketones give alcohols, reaction with acid chlorides and esters give tertiary alcohols, reaction with carbon dioxide to give carboxylic acids, reaction with nitriles give ketones, and reaction with epoxides give alcohols. 

Mechanism of the reaction of a Grignard reagent with a nitrile to produce a ketone. 

Li2CuCl4 in THF-NMP efficiently catalyzes the reaction of alkenyl Grignard reagents with primary alkyl bromides. Functional groups (ketone, ester, nitrile, sulfonate) are tolerated in this reaction (Scheme 34).91... 

Aromatic carboxylic acids can be prepared by oxidation of the corresponding benzyl alcohols and benzaldehydes. An aromatic methyl group is also sufficiently activated by the aromatic ring for it to be oxidized to the acid under vigorous conditions, such as heating with chromium(VI) oxide. Other conventional methods include the hydrolysis of aromatic nitriles and the carboxylation of aromatic Grignard reagents with carbon dioxide. 

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