Nitriles from cyanide

The direct synthesis of aryl- or alkyl nitriles from cyanide and organohalide precursors is revered in synthetic chemistry, as the nitriles represent a flexible functionality that can easily be converted into (for example) carboxylic acids, esters, amides, amidines, amines and various hetero cycles [67], such as thiazoles, oxazolidones, triazoles and tetrazoles [68]. The tetrazole group... 

Hydrolysis of a nitrile to an amide. Warm a solution of 1 g. of the nitrile benzyl cyanide) in 4 ml. of concentrated sulphuric acid to 80-90°, and allow the solution to stand for 5 minutes. Cool and pour the solution cautiously into 40 ml. of cold water. Filter oflT the precipitate stir it with 20 ml. of cold 5 per cent, sodium hydroxide solution and filter again. RecrystaUise the amide from dilute alcohol, and determine its m.p. Examine the solubility behaviour and also the action of warm sodium hydroxide solution upon the amide. 

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 ... 

The reaction works well with primary alkyl halides, especially with allylic and benzylic halides, as well as other alkyl derivatives with good leaving groups. Secondary alkyl halides give poor yields. Tertiary alkyl halides react under the usual reaction conditions by elimination of HX only. Nitriles from tertiary alkyl halides can however be obtained by reaction with trimethylsilyl cyanide 4 ... 

The asymmetric Strecker synthesis of a-amino nitriles from Schiff bases of a-methylbenzyl-aminc is improved by the use of trimethylsilyl cyanide, instead of hydrogen cyanide and by promotion of the transformation with a Lewis acid, preferably zinc chloride43. Thus, from the butyraldimine 2, the amino nitrile is synthesized with a yield of 98.5% and an ee of 68.5%. 

Nickel, dichloro [ethylenebis(dimethyl-phosphine)], 58, 133 Nickel, dichloro[ethj lenebis(diphenyl-phosphine)], 58,133 [Ni (-)-diop Cl2 ], (-)-diop=2,3-0-iso-propylidene-2,3-dihydroxy-l,4-bis(di-phenylphosphino)butane, 58, 133 Nickel, dichloro [ trimethylenebis(diphenyl-phosphine)], 58,133 NITRILES, alkylation of, 55, 91 NITRILES FROM KETONES, 58, 101 NITRILES, a vinyl, 55, 99, 101 p-Nitrobenzenesulfonyl cyanide, 57, 89 p-Nitrobenzyl alcohol, 57, 72 p-NITROBENZYL FLUORIDE, 57, 72 Nitro compounds, 56, 36 Nitronates, 56, 36... 

PELOUZE SYNTHESIS. Formation of nitriles from alkali cyanides by alkylation with alkyl sulfates of alkyl phosphates. 

Acrylonitrile (2-propenonitrile, propene nitrile, vinyl cyanide, CH2=CHCN freezing point -83.5°C, boiling point 77.3°C, density 0.806) used to be manufactured completely from acetylene by reaction with hydrogen cyanide. 

Thiocyanate ions, cyanide ions and nitrite ions can each react with an electrophile R+, depending upon its nature and the conditions, to give either of two products a thiocyanate 4.24 or an isothiocyanate 4.25 from the thiocyanate ion, an isonitrile 4.26 or a nitrile 4.27 from cyanide ion, and an alkyl nitrite 4.28 or a nitroalkane 4.29 from nitrite ion. Each is nucleophilic at more than one site, and nucleophiles like these are called ambident. 

NIOSH REL (Nitriles) CL 6 mg/mVl5M SAFETY PROFILE Poison by ingestion, intraperitoneal, and intravenous routes. An experimental teratogen. A human skin irritant and allergen. In the preparation of sponge rubber, an azo compound is used that decomposes to form tetramethylsuccinonitrile or TMSN. Rats exposed to a concentration of 90 ppm exhibit their first convulsion after 1.5-2 hours or less. Rats exposed to concentration of 5.5 ppm exhibited their first convulsions in 27-31 hours and were dead in 31-46 hours. Absorbed by skin. The fatal dose in humans is thought to be about 25 mg/kg of body weight. TSN is slowly detoxified by the body. This nitrile is different from other nitriles in that thiosulfate is a poor antidote for intoxication. When heated to decomposition it emits toxic fumes of CN and NOx. See also NITRILES and CYANIDE. 

The formation of olefinic nitriles from allylic halides is best accomplished with dry, powdered cuprous cyanide rather than with alcoholic alkali cyanides, with which side reactions such as isomerization and alcoholysis of the double bond are particularly bothersome. With cuprous cyanide the yields in the synthesis of allyl cyanide and methal-lyl cyanide are 84% and 86%, respectively. Higher allylic halides are subject to allylic rearrangements thus cuprous cyanide acts on crotyl halide (CH,CH CHCHjX) and methylvinylcarbinyl halide (CH,CHXCH = CH,) to produce the same mixture of isomeric nitriles (9 1) regardless of which halide is treated. Numerous cyanides of the allylic type (Cj-Ci4) have been prepared, although the possibility of an isomerization has not been considered. A similar isomerization has been observed in the reaction of sorbyl chloride and potassium cyanide. ... 

A synthesis of nitriles from the cyanohydrins of aromatic aldehydes via the reduction of the corresponding a-halo cyanides has been proposed. As an example, benzaldehyde cyanohydrin is converted by the action of thionyl chloride to phenylchloroacetonitrile (80%). This substance is reduced with zinc in acetic acid to phenylacetonitrile (70%). ... 

Mechanism 28.1 for the formation of the a-amino nitrile from an aldehyde (the first step in the Strecker synthesis) consists of two parts nucleophilic addition of NH3 to form an imine, followed by addition of cyanide to the C=N bond. Both parts are related to earlier mechanisms involving imines (Section 21.11) and cyanohydrins (Section 21.9). 

Nitriles from Sulphonic Acids or Aiyl Halides.—Individual acid nitriles will be mentioned at various times whenever they are used in preparing various acids. Several reactions may be employed to prepare the nitriles in which the cyanogen group is in the ring. The simplest method is from sulphonic acids by heating with potassium cyanide. 

Nitriles from Iso-thio-cyanates.— The nitriles may also be made from iso-thio-cyanates (p. 73). When these are heated with copper the sulphur is eliminated and the iso-cyanides ox iso-nitriles are obtained and these iso-cyanides are transformed into the cyanide or nitrile. 

In addition to its use in the preparation of nitriles, trimethylsilyl cyanide (TMS-CN) is also becoming a very useful reagent for the preparation of isocyanides. 1-Chloroadamantane, for instance, gives rise to 78% of the corresponding isonitrile in the presence of catalytic amounts of TiCU (Scheme 26). Of special interest is the remarkably regioselective and stereoselective synthesis of trimethylsilyloxyalkyl isocyanides (Scheme 26) from oxiranes and TMS-CN in the presence of, for example, zinc halides (see also Section 1.8.1.3). < ... 

By this method, 1-bromonaphthalene affords 1-naphthonitrile in 94% yield after refluxing for 4 hrs. with pyridine as solvent the reaction mixture is heated in an oil bath at 215-225° for 15 hrs., and the yield is 82-90%. Efficient procedures for liberating the nitrile from the cuprous halide complex involve pouring the brown reaction mixture into an aqueous solution of ferric chloride (oxidizes Cu+ to Cu ", which forms no complex), ethylenediamine (forms complexes with Cu+ and Cu " ), or sodium cyanide (forms soluble sodium cuprocyanide). The higher-boiling N-methyl-2-pyrrolidone (b.p, 202°) is also satisfactory, but is more expensive. 

Rosenmund—von Braun synthesis. Formation of aromatic nitriles from aryl halides and cuprous cyanide. 

Recently, the group of Herrera, Bernardi, and Ricci realized the enantioselective synthesis of protected a-amino nitriles from the corresponding a-amino sulfones 137, which act as effective precursors for the in situ generation of imines, by the use of acetone cyanohydrin (138) as a cyanide source using quinine-derived PTC 136 [64]. The aminonitriles 139 were produced with broad generality in 50-88% ee (Scheme 8.53). However, a similar protocol using KCN and TMSCN resulted in a lower ee value. 

There is considerably more information about nitriles from natural gas or petroleum this is to be expected since there are two distinct routes to these substances—from hydrogen cyanide and a hydrocarbon (CeHe + HCN - C H5CN -H H2) and from the pyrolysis of ammonia and hydrocarbons, particularly low-carbon number hydrocarbons, as in CHj + NH3 + CftHe - CeHfcCN 4- 4H2. The latter process is reviewed by Groggins (7), and is extended to imsaturated hydrocarbons. Both acetonitrile and acrylonitrile are so obtained industrially. 

Cuprous cyanide Nitriles from halides s. 2, 728 3, 687 CuCN Hal -V CN... 

This method of reaction is also applicable to the preparation of hydroxy nitriles (from chlorohydrins, yields about 80%)452 and a-alkoxy nitriles (from -halo ethers and copper cyanide, yields 55-80%).453... 

An improvement of the palladium-catalyzed cyanation of aryl bromides, in which zinc cyanide was used as the cyanide source, was reported in the middle of the nineties [105]. Typically, conversion from halide to nitrile required at least 5 h by this method and the subsequent cycloaddition to the tetrazole is known to require even longer reaction times. The Hallberg group has described a single-mode MW procedure, using zinc cyanide, for palladium-catalyzed preparation of both aryl and vinyl nitriles from the corresponding bromides [106]. The reaction times were short and full conversion was achieved in just a few minutes (Scheme 15.51). 

Reactions of Oxazoles. The reaction of 4-phenyloxazole with di(acetoxy-methyl)acetylene gives the furan (531 R = CH2OAC) by extrusion of benzo-nitrile from the intermediate Diels-Alder adduct (530 R = CH20Ac). Similarly, 5-cyano-4-methyloxazole and hept-l-yne yield mainly the furan (532) and methyl cyanide a minor product, the 4-substituted isomer (533), arises from the alternative mode of addition of the acetylene. The sensitized photooxidation of 2,4-diphenyl-2-oxazolin-5-one (534) affords, inter alia, the coupled product (535). ... 

Acute and subchronic toxicity, teratogenicity, and biochemical mechanism studies of a series of structurally similar aliphatic nitriles indicated that although the toxicological profiles were generally the same for most of the compounds, there were unique differences, too (Johannsen and Levinska, 1986). In this respect, acetonitrile was different from the other nitriles within the homologous series. Nitriles liberated cyanide both in vivo and in vitro. Tanii and Hashimoto (1984a,b, 1985) observed a dose-cyanide liberation relationship in liver and hepatic microsomal enzyme system in mice pretreated with carbon tetrachloride. For most nitriles, the toxicity was greatly reduced by carbon tetrachloride pretreatment. By contrast, certain nitriles, exhibited an increase of toxicity as a result of such pretreatment. 

Retrosynthetically, a base-catalyzed dimerization of 127 would afford stephacidin B. Avrainvillamide (127) was simplified as vinyl iodide 128 by cleavage of the dihydropyrano [2,3-g]indole-l-oxide moiety and palladium mediated coupling. An aminoacyl radical addition from 129 gave access to 128, while 129 could be derived from cyanide 130 through a hemiaminal formation/dehydration and conjugate addition. Finally, Strecker-like reaction of ketone 131 would fulfill nitrile 130 [55] (Scheme 22). 

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