Nitriles preparation reactions

Nitdles may be prepared by several methods (1). The first nitrile to be prepared was propionitdle, which was obtained in 1834 by distilling barium ethyl sulfate with potassium cyanide. This is a general preparation of nitriles from sulfonate salts and is referred to as the Pelou2e reaction (2). Although not commonly practiced today, dehydration of amides has been widely used to produce nitriles and was the first commercial synthesis of a nitrile. The reaction of alkyl hahdes with sodium cyanide to produce nitriles (eq. 1) also is a general reaction with wide appHcabiUty ... 

Carboxylic acids can be prepared from nitriles by reaction with hot aqueous acid or base by a mechanism that we ll see in Section 20.9. Since nitriles themselves are usually made by Sts 2 reaction of a primary or secondary7 alkyl halide with CN , the two-step sequence of cyanide displacement followed by nitiile hydrolysis is a good way to make a carboxylic acid from an alkyl halide (RBr —> RC=N RC02H). 

The simplest method of nitrile preparation is the Sj 2 reaction of CN with a primary or secondary alkyl halide, as discussed in Section 20.5. Another method for preparing nitriles is by dehydration of a primary amide, RCONH2. Thionyl chloride is often used for the reaction, although other dehydrating agents such as POCI3 also work. 

As noted in Section 11.2.2, nucleophilic substitution of aromatic halides lacking activating substituents is generally difficult. It has been known for a long time that the nucleophilic substitution of aromatic halides can be catalyzed by the presence of copper metal or copper salts.137 Synthetic procedures based on this observation are used to prepare aryl nitriles by reaction of aryl bromides with Cu(I)CN. The reactions are usually carried out at elevated temperature in DMF or a similar solvent. 

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

Thioamides have been transformed into the corresponding nitriles. Treatment of primary thioamides by tellurium tetrachloride or selenium tetrachloride in combination with triethylamine affords nitriles.66 Treatment of primary amides and thioamides with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) gives nitriles.67 Reactions of thioamides with metal carboxylates in organic solvents enables the selective preparation of nitriles, imides or amides depending on the substitution pattern of the starting material (Scheme 33).68... 

A number of organic species, including amides, oximes, and nitriles, undergo reductive amination, a variety of reduction reactions that produce cimines. In general, these processes involve imines, R=N-R, or related species. Reduction processes include hydrogenation using Raney nickel as the catalyst (for nitriles), the reaction with sodium/EtOH (for oximes), and the use of lithium aluminum hydride, LiAlH (for amides or nitriles). Figure 13-16 illustrates the preparation of amphetamine by reductive amination. 

A somewhat similar method of cyanide preparation is applicable in the aromatic series aromatic sulphonic acid potassium salts, on fusion with potassium cyanide or potassium ferrocyanide, yield aromatic nitriles. The reaction can be extended to derivatives of pyridine. 

Table 3 Preparation of Peptidyl Nitriles by Reaction of Benzotriazole Adducts with Alkali Cyanide 1 1...

Aromatic ketones arylations, 10, 140 asymmetric hydrogenation, 10, 50 G—H bond alkylation, 10, 214 dialkylzinc additions, 9, 114-115 Aromatic ligands mercuration, 2, 430 in mercury 7t-complexes, 2, 449 /13-77-Aromatic nitriles, preparation, 6, 265 Aromatic nucleophilic substitution reactions, arene chromium tricarbonyls, 5, 234... 

A few examples will show the importance of these reactions in synthetic organic chemistry. If X is an alkoxide ion, equation (1) describes the Williamson ether synthesis (2). If X is a cyanide ion, (1) describes a standard nitrile preparation (3). If X is an aromatic nucleus, and the departure of the leaving group is facilitated by A1C13, then (1) describes the Friedel-Crafts alkylation (4). With X as the cyanate ion, (1) describes the preparation of isocyanates (5) and if it is ammonia, (1) describes a common method of preparation of amines (6). In addition, nucleophilic transmethylation is a very... 

Tlie nitrile, prepared as above, is next digested with the calculated amount of sodium malonic ethyl ester, on the water-bath, till no alkaline reaction is obtained. After removal of the alcohol aud sodium chloride, the cyano-propyl-malonic ethyl ester is fractionally distilled nnder reduced pressure. B.p. 170°—175° at 40 mm. 

Reaction mann reactions (Figure 16.4-16.6). Regarding the preparation of aromatic nitriles, this reaction presents an alternative to the Sandmeyer reaction of aryl diazonium salts with CuCN (cf. Figure 5.53). 

Action of Carbon Disulfide on CH-Acidic Nitriles The reaction of carbon disulfide with alkylidene malononitriles (27) or alkylidene cyanoacetic acid esters (28), in dimethyl formamide in the presence of triethylamine, leads to aminodithiopyrones (29) in high yields.36,86 The preparation may also be realized directly,... 

The simplest method of nitrile preparation is S, -2 reaction of CN withs primary alkyl halide, as discus in Section 20.6. Hus method is Itocled by the usual Sx2 steric oonstrauiu to the synthesis of u-umidiKiUitRl nitriles. RCKjCN. 

A few 6- and 8-cyanopurines have been prepared and undergo characteristic nitrile addition reactions rather readily. Thus, alkaline hydrolysis produces carboxamides, then carboxylic acids, alcoholysis leads to imidates, ammonolysis to amidines, hydrazinolysis to amidhydrazines, hydroxylamine to amidoximes, and hydrogen sulfide to thioamides. Acid hydrolysis tends to give the decarboxylated acid derivative. Reduction either by sodium-ethanol or, preferably, by catalytic hydrogenation affords aminoalkylpurines and addition of Grignard reagents produces, in the first place, acylpurines. As with aldehydes, most of the compounds examined have been relatively non-polar derivatives. Table 28 lists some reactions and relevant literature. 

Thanks to the ready availability of nitriles, their reaction with nitrilimines is a useful method for the preparation of bistriazoles, e.g. (189) and (190) in Scheme 89. 

The acylsilane toxylhydrazones exhibit slightly less positive oxidation potentials than the corresponding tosylhydrazones of aldehydes [137]. The preparative anodic oxidation of acylsilane tosylhydrazones in a divided cell gave the corresponding nitriles. This reaction seems to be promoted by the electrogenerated acid. 

---