Hydrolysis of alkyl cyanides

Since alkyl cyanides are readily available from the interaction of alkyl halides with sodium or potassium cyanide in aqueous alcoholic solution (Expts 5.157 and 5.158), their hydrolysis to carboxylic acids is a valuable synthetic method. Aqueous alkaline or acidic conditions may be used. The reaction proceeds via the intermediate formation of an amide. Experimental conditions may be selected to interrupt the hydrolysis at the amide stage (Expt 6.167). 

As well as the illustrative synthesis of a simple carboxylic acid (pentanoic acid, Expt 5.127), examples are given of the synthesis of some dicarboxylic acids, aryl substituted carboxylic acids, and the unsaturated acid, vinylacetic acid (Expt 5.128). 

The nitrile group in the readily available a-hydroxynitriles (the cyanohydrins) may also be similarly hydrolytically converted into a carboxyl group to afford a convenient synthesis of a-hydroxy acids (Expt 5.168). 

In a 2-litre round-bottomed flask, equipped with a double surface condenser, place 60 g (0.64 mol) of pentanedinitrile (Expt 5.157) and 900 g of 50 per cent sulphuric acid (by weight). Reflux the mixture for 10 hours and allow to cool. Saturate the solution with ammonium sulphate and extract with four 150 ml portions of ether dry the ethereal extracts with anhydrous sodium sulphate. Distil off the ether on a water bath the residual glutaric acid (69 g, 82%) crystallises on cooling and has m.p. 97-97.5 °C. Upon recrystallisation from chloroform, or benzene, the m.p. is 97.5-98 °C. 

Cognate preparations. Suberic acid (octanedioic acid). Heat a mixture of octanedinitrile (Expt 5.157) with 15 times its weight of 50 per cent sulphuric acid by weight under reflux for 10 hours. The acid crystallises out on cooling. Filter off- the suberic acid upon a sintered glass funnel, and recrystallise it from acetone m.p. 141-142 °C. The yield is 90 per cent of the theoretical. 

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By hydrolysis of alkyl cyanides (or nitriles) with alkali hydroxide solutions, for example ... 

Organic acids can be prepared in many ways, four of which are described here (1) oxidation of primary alcohols or aldehydes, (2) oxidation of alkyl side chains on aromatic rings, (3) reaction of Grignard reagents with carbon dioxide, and (4) hydrolysis of alkyl cyanides (nitriles). 

Nitrile groups m cyanohydrins are hydrolyzed under conditions similar to those of alkyl cyanides Cyanohydrin formation followed by hydrolysis provides a route to the preparation of a hydroxy carboxylic acids... 

Pyruvic acid is the simplest homologue of the a-keto acid, whose established procedures for synthesis are the dehydrative decarboxylation of tartaric acid and the hydrolysis of acetyl cyanide. On the other hand, vapor-phase contact oxidation of alkyl lactates to corresponding alkyl pyruvates using V2C - and MoOa-baseds mixed oxide catalysts has also been known [1-4]. Recently we found that pyruvic acid is obtained directly from a vapor-phase oxidative-dehydrogenation of lactic acid over iron phosphate catalysts with a P/Fe atomic ratio of 1.2 at a temperature around 230°C [5]. 

Probably the most important group of phase transfer reactions, and certainly the commonest, are those in which an anion is transferred from the aqueous phase into the organic solvent, where nucleophilic substitution occurs. These would once have been performed in a dipolar aprotic solvent such as DMF. A good example is the reaction between an alkyl halide (such as 1-chlorooctane), and aqueous sodium cyanide, shown in Scheme 5.5. Without PTC, the biphasic mixture can be stirred and heated together for 2 weeks and the only observable reaction will be hydrolysis of the cyanide group. Addition of a catalytic amount of a quaternary onium salt, or a crown ether, however, will lead to the quantitative conversion to the nitrile within 2 h. 

In all of these mixed compounds, the substances possess the properties of both kinds of substitution products represented. The halogen nitro compounds, on reduction, yield halogen amines. The halogen amines are basic compounds, like the amines themselves, and form salts with mineral acids. The halogen cyanogen compounds possess the nitrile properties of alkyl cyanides, and on hydrolysis yield halogen acids. The cyanogen amines are, similarly, both acid nitriles and... 

For those nitriles which yield water-insoluble amides e.g., the higher alkyl cyanides), hydrolysis to the amide often leads to a satisfactory derivative. The hydration is eflfected by warming a solution of the nitrile in concentrated sulphuric acid for a few minutes, cooling and pouring... 

Primary and secondary alkyl halides may be converted to the next higher carboxylic acid by a two step synthetic sequence involving the preparation and hydrolysis of nitriles Nitnles also known as alkyl cyanides are prepared by nucleophilic substitution... 

Methylsuccinic acid has been prepared by the pyrolysis of tartaric acid from 1,2-dibromopropane or allyl halides by the action of potassium cyanide followed by hydrolysis by reduction of itaconic, citraconic, and mesaconic acids by hydrolysis of ketovalerolactonecarboxylic acid by decarboxylation of 1,1,2-propane tricarboxylic acid by oxidation of /3-methylcyclo-hexanone by fusion of gamboge with alkali by hydrog. nation and condensation of sodium lactate over nickel oxide from acetoacetic ester by successive alkylation with a methyl halide and a monohaloacetic ester by hydrolysis of oi-methyl-o -oxalosuccinic ester or a-methyl-a -acetosuccinic ester by action of hot, concentrated potassium hydroxide upon methyl-succinaldehyde dioxime from the ammonium salt of a-methyl-butyric acid by oxidation with. hydrogen peroxide from /9-methyllevulinic acid by oxidation with dilute nitric acid or hypobromite from /J-methyladipic acid and from the decomposition products of glyceric acid and pyruvic acid. The method described above is a modification of that of Higginbotham and Lapworth. ... 

Treatment of a-(benzotriazol-l-yl)alkyl thioethers 831 with ZnBr2 weakens the bond with benzotriazole, and the obtained complex 832 may partially dissociate to thionium cation 835 that can be trapped by even mild nucleophiles. Thus, trimethylsilyl cyanide added to the reaction mixture causes substitution of the benzotriazole moiety by the CN group to give a-(phenylthio)carbonitrile 834. In a similar manner, treatment with allylsilane leads to y,S-unsaturated thioether 833. Addition of species 835 to the double bond of a trimethylsilyl ot-arylvinyl ether followed by hydrolysis of the silyloxy group furnishes (i-(phenylthio)alkyl aryl ketones 836 (Scheme 132) <1996TL6631>. 

Another way to synthesize ibuprofen consists of the chloromethylation of Ao-butylben-zene, giving 4-Ao-butylbenzylchloride (3.2.24). This product is reacted with sodium cyanide, making 4-Ao-butylbenzyl cyanide (3.2.25), which is alkylated in the presence of sodium amide by methyl iodide into 2-(4-iAo-butylbenzyl)propionitrile (3.2.26). Hydrolysis of the resulting product in the presence of a base produces ibuprofen (3.2.23). 

Reaction XLVm. (a) Action of Alkali Cyanides on Alkyl and Acyl Halides. (Bl., [2], 50, 214.)—This reaction is capable of very wide application, all the simple alkyl halogen compounds, the acyl halides, and the halogen fatty acids come within its scope. The nitriles so formed yield acids by hydrolysis, so it is frequently the first step in the synthesis of an acid—the preparation and hydrolysis of the nitrile are often combined. The preparations of malonic, succinic, tricarballylic and other acids (Preparations 60, 61, 62) illustrate this. The extension of this reaction to acyl halides is important, and should be referred to, as should the interaction of silver cyanide, and alkyl iodides, to give isonitriles. Mercuric and silver cyanides, it may be noted, give with acyl chlorides and bromides better yields of normal acyl nitriles than do the alkali cyanides. 

The preparation of amides by the addition of hydrogen cyanide or alkyl nitriles to alkenes in the presence of acids, known as the Ritter reaction, has been reviewed.229-232 The reaction may be considered simplistically as nucleophilic attack of a nitrile on a carbocation formed by the protonation of an alkene. Subsequent hydrolysis of the nitrilium intermediate gives the amide product (equation 164). The overall result is addition of a molecule of H—NHCOR to a C—C double bond. 

Another way to convert an alkyl halide (or tosylate) to a carboxylic acid with an additional carbon atom is to displace the halide with sodium cyanide. The product is a nitrile with one additional carbon atom. Acidic or basic hydrolysis of the nitrile gives a carboxylic acid by a mechanism discussed in Chapter 21. This method is limited to halides and tosylates that are good SN2 electrophiles usually primary and unhindered. 

Two of the methods for converting alkyl halides to carboxylic acids are covered in Sections 20-8B and 20-8C. One is formation of a Grignard reagent followed by addition of carbon dioxide and then dilute acid. The other is substitution by cyanide ion, followed by hydrolysis of the resulting nitrile. For each of the following conversions, decide whether either or both of these methods would work, and explain why. Show the reactions you would use. 

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