Alkyl halides with cyanide

Section 20 18 Nitnles are prepared by nucleophilic substitution (8 2) of alkyl halides with cyanide ion by converting aldehydes or ketones to cyanohydrins (Table 20 6) or by dehydration of amides... 

Chain extension by means of the reaction of alkyl halides with cyanide is frequently alluded to but rarely employed, mainly because of the long reaction times and poor yields usually encountered. The use of DMSO as a solvent has greatly simplified the procedures and improved the yields of many ionic reactions, and the conversion of alkyl chlorides to nitriles is a good example. 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Reactions at o -Position. Many studies have been concerned with the reactions of alkyl halides with cyanide in the presence of various metal ions, and with the direct alkylation of cyanide complexes. The classic synthesis of isonitriles was accomplished by the use of silver cyanide, whereas the corresponding reaction of organic halogen compounds with alkali cyanides yields nitriles (Equations 40 and 41) (34,36). 

The reaction of an alkyl halide with cyanide ion involves nucleophilic substitution (Sec. 14.5). The fact that HCN is a very weak acid tells us that cyanide ion is a strong base as we might expect, this strongly basic ion can abstract hydrogen ion and thus cause elimination as well as substitution. Indeed, with... 

Nitriles, R-C=N, can be hydrolyzed by strong, hot aqueous acid or base yield carboxylic acids. Since nitriles themselves are usually prepared by reaction of an alkyl halide with cyanide ion, the two-step sequence of cyanide displacement followed by nitrile hydrolysis is an excellent method for preparing a carboxylic acid from an alkyl halide (RBr —> RCsN — RCOOH). Note that the product acid has one more carbon than the starting alkyl halide. 

The transformation of alkyl halides with cyanides (equation 1) represents not only the classical route to nitriles, but, if modified properly, is still of very great practical importance even today. A whole series of review articles stress the scope and value of this reaction. Although the substituent R may be varied to a large extent, the primary as well as the benzylic halides generally give higher yields than secondary and tertiary ones, as, with the latter, the formation of alkenes gains in importance. This side reaction as well as the undesired formation of alcohols and ethers, which sometimes takes place in aqueous media or with alcohols as solvent, is of course due to the basicity of the cyanide ion. Under deleterious conditions one may even observe carboxylic acids, which result fi-om the hydrolysis of the nitriles. - Some of these undesired side reactions may be avoided by the use of CuCN instead of sodium or potassium cyanide. ... 

As will be shown, a whole range of variations and modifications is known for the reaction of alkyl halides with cyanide ions (equation 4). Without trying to cover every detail, an attempt will be made to mention the most important procedures and to give a few typical examples (see Tables 1 and 2). Despite the diversity of the reaction conditions, a general comparison of their synthetic importance is useful. 

The synthesis of secondary nitriles by the reaction of secondary alkyl halides with cyanide ion is a process which normally gives poor results. Two methods have been introduced to circumvent this difficulty, in each case a ketone is the starting material. The first method consists of converting a ketone to its tosyl hydrazone which adds HCN to give (48) in excellent yield. The decomposition of this product was attempted with basic reagents but the yield was poor (20-30%) however, good results were obtained by adding (48) to a bath of decalin maintained at 180°. Decomposition was complete in two hours and for the two examples quoted (cyclohexanone and heptan-4-one) yields of 60% were obtained [122],... 

Substitution and Addition Reactions. All types of reactions between inorganic anions and organic partners can be executed under the PTC conditions. Nucleophilic aliphatic substitution in alkyl halides with cyanide anions to form nitriles was presented in the Introduction as a typical example of PTC on which the basic principles and characteristic features of this catalysis were discussed. 

Nitriles can be prepared from an Sn2 reaction of alkyl halide with cyanide ion. Because a nitrile can be hydrolyzed to a carboxylic acid, you now know how to convert an alkyl halide into a carboxylic acid. Notice that the carboxylic acid has one more carbon than the alkyl halide. 

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