Nitrile amide dehydration

Both methods of nitrile synthesis—SN2 displacement by CN- on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. 

Racemic 2-ethylhexanonitrile has been obtained only by the action of phosphorus pentachloride on 2-ethylhexanaldoxime 4 the levorotatory form has been prepared from the active amide by the method described.6 Other amides have been converted to nitriles by dehydration with thionyl chloride.6-6... 

Scheme 1 Peptide Nitriles by Dehydration of Peptide Amides...

Ferrini and Marxer65 have recently shown that vinylene carbonate reacts with primary amides, in the presence of polyphosphoric acid, to yield 2-substituted oxazole derivatives. Yields are low (2-34%), and phenoxy- and phenyl-acetamide, p-methylbenzamide, and salicylamide do not give oxazole derivatives. Although the reaction has been interpreted according to Scheme 3, the nucleophilic attack of a nitrile molecule (from the amide dehydration), with a nitrilium salt as intermediate (Scheme 4), cannot be excluded.06... 

The adduct of DMF and dichlorophenylphosphine has been used to convert primary aromatic amides to nitriles by dehydration," as well as to synthesize 2,5-diaryl-1,3,4-oxadiazoles from A iV -diacylhydra-zides. ... 

The nitrile functional group is, formally, a dehydrated primary amide. (In fact, u little-used nitrile synthesis involves amide dehydration ... 

The mixture of the isomers of trimethyladipic acids is treated with ammonia, converted to amides, dehydrated to nitriles, and reduced to amines ... 

In the selection of the drying agent, care must always be taken that it does not attack the solvent itself. For example, in dehydrations with lithium aluminium hydride, it is not only water which reacts with the drying agent the hydride also reduces aldehydes, ketones and esters to alcohols, and nitriles, amides and aldimides to amines. It is naturally not suitable, therefore, for the dehydration of solvents having such chemical composition. 

Efficient methods for the synthesis of nitriles by dehydration of aldoximes and primary amides have been developed. " The reactions were performed in the presence of a Lewis acid ionic liquid, a uranium, or a copper catalyst. 

An approach that was not very successful saw a carbamate isoasparagine derivative (1.236) converted to a nitrile via dehydration of the amide moiety. Removal of the protecting group gave 3-amino-3-cyano-propanoic acid (7.237). This approach was also used to prepare 4-amino-4-cyanobutanoic acid, but the yield of amino acid was again very poor. Introduction of a cyano group in this particular way does not appear to be a good synthetic procedure. 

Kim SH, Kim SH, Kim JN, Kim TH (2010) Synthesis of 4-aUylquinazolines from N- 2-cyanoaryl)amides via the In-mediated allylation of nitrile and dehydrative cyclization cascade. Tetrahedron Lett 51 2774-2777... 

Certain secondary and tertiary alcohols are dehydrated to olefins, under the influence of H2SO4. These can then polymerize to give polymers insoluble in concentrated sulfuric acid. In spite of this, such compounds are classified into groups 6 or 7. In homologous series of monofunctional compounds (ethers, esters, ketones, alcohols, nitriles, amides, acids, amines) substances with 5 C in the molecule are usually soluble in water those with branched carbon chains are more soluble. 

Fatty amines are produced by h. of - fatty nitriles, which are derived from - fatty acid and ammonia via the amide. Dehydration of the amide is the first step to yield the nitrile, which is hydrogenated in the presence of a catalyst. Aside from Ni and Co, noble metals and iron are used as catalysts in batch processes with suspended catalyst and in continuous processes with a fixed-bed catalyst. 

Nitriles and Isocyanides via Amide Dehydration. Thionyl chloride dehydrates primary amides to form nitriles (eq 8) for example, 2-ethylhexanonitrile is produced in about 90% yield by heating with SOCI2 in benzene. Substituted benzonitriles are readily produced from benzamides. These reactions may also be catalyzed by DMF. A -Alkylformamides may be dehydrated to isocyanides. ... 

Substituted hydroxamic acids successfully cyclize to form 3-lactams as long as EtsN is present (eq 19). In the absence of the base, complex mixtures are formed. Unsubstituted amides can be converted into nitriles via dehydration (eq 20). This is the reagent of choice for the transformation of the amide to the nitrile in eq 21. ... 

At temperatures of 220-240 C it functions as an efficient, neutral dehydrating agent, amides yielding nitriles and alcohols yielding alkenes. 

Cyanothiazoles can be prepared by different methods. Dehydration of amides to give nitriles has already been mentioned. The yields are good... 

Both alkyl and aryl nitriles are accessible by dehydration of amides... 

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 ... 

In general, the reactions of the perfluoro acids are similar to those of the hydrocarbon acids. Salts are formed with the ease expected of strong acids. The metal salts are all water soluble and much more soluble in organic solvents than the salts of the corresponding hydrocarbon acids. Esterification takes place readily with primary and secondary alcohols. Acid anhydrides can be prepared by distillation of the acids from phosphoms pentoxide. The amides are readily prepared by the ammonolysis of the acid haUdes, anhydrides, or esters and can be dehydrated to the corresponding nitriles (31). 

The zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Hydrolysis of primary amides cataly2ed by acids or bases is very slow. Even more difficult is the hydrolysis of substituted amides. The dehydration of amides which produces nitriles is of great commercial value (8). Amides can also be reduced to primary and secondary amines using copper chromite catalyst (9) or metallic hydrides (10). The generally unreactive nature of amides makes them attractive for many appHcations where harsh conditions exist, such as high temperature, pressure, and physical shear. 

Nitrile Process. Fatty nitriles are readily prepared via batch, Hquid-phase, or continuous gas-phase processes from fatty acids and ammonia. Nitrile formation is carried out at an elevated temperature (usually >250° C) with catalyst. An ammonia soap which initially forms, readily dehydrates at temperatures above 150°C to form an amide. In the presence of catalyst, zinc (ZnO) for batch and bauxite for continuous processes, and temperatures >250° C, dehydration of the amide occurs to produce nitrile. Removal of water drives the reaction to completion. 

Amides react ia certain cases to form ammonium salts of sulfonated amides (22). For example, treatment with ben2amide yields ammonium A/-ben2oylsulfamate [83930-12-5] C H CONHSO NH, and treatment with ammonium sulfamate yields dianmioiiiumimidodisulfonate [13597-84-17, HN(S020NH 2 Ammonium sulfamate or sulfamic acid and ammonium carbonate dehydrate Hquid or soHd amides to nitriles (27). 

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