Primary amides, dehydration

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. 

Primary amides are dehydrated to nitriles using a dehydrating agent like thionyl chloride (SOCl3), phosphorus pentoxide (P2Os), phosphoryl trichloride (POCl3), or acetic anhydride o... 

Amides - nitriles. Primary acid amides are dehydrated to nitriles by treatment with titanium tetrachloride and a base (triethylamine, N-mcthylmorpholine) in THF at 0°. Yields range from 65 to 95%. 

Nitriles. Primary amides are dehydrated under the Swem oxidation conditions. 

In structural studies on oxytetracycline (Terramycin) and chlorotetracycline (Aureomycin) a Pfizer group found that tosyl chloride in cold pyridine converts the antibiotics into nitrile derivatives through dehydration of the primary carbox-amido group. They then found that simpler amides are dehydrated to nitriles in good yield by adding 1 equivalent of tosyl chloride slowly to a mixture of the amide with 2.25 equivalents of pyridine at a rate such as to maintain a temperature of about 70°. The mechanism proposed involves O-tosylation. 

No reaction occurs with secondary amides. Primary amides, on the other hand, are dehydrated to nitriles ... 

Dihalocarbenes produced under PTC conditions have been advantageously used in the classical isonitrile synthesis from primary amines, again giving higher yields than the classical procedure. Hydrazine affords diazomethane, amides are dehydrated to nitriles and sulfoxides are reduced to sulfides in high yields. Finally, alcohols are converted into halides (Table 17)... 

Nitriles are acid derivatives. Primary amides are dehydrated to nitriles, and nitriles are hydrolyzed to either an amide or a carboxylic acid. 

The ester derivatives of nitric acid, sulfuric acid, and phosphoric acid are important compounds, with some use in organic chemistry but greater use in biology 81,82,83,137,138,139,140. Nitriles are acid derivatives. Primary amides are dehydrated to nitriles, and nitriles are hydrolyzed to either an amide or a carboxylic acid 84,85,96,108,126,129. 

By the dehydration of amides, primary, secondary, and tertiary nitriles can be obtained in good yields. 

Nitriles from Amides. Primary amides are dehydrated to afford nitriles upon heating with PCls. Due to the severity of the reaction conditions, substrates of limited functional complexity are tolerated. The reactions are generally conducted either neat or with POCI3 as a solvent. This method is useful for products... 

By the dehydration of primary amides with phosphorus pentoxide or with thionyl chloride, for example ... 

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 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. 

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. 

The dehydration of primary amides with hydrosilane catalyzed by iron carbonyl clusters, such as [Et3NH][HFe3(CO)n] and Fe2(CO)9, was achieved by Seller and coworkers in 2009 (Scheme 43) [145]. This reaction shows good functional group tolerance (e.g., such as aromatic, heteroaromatic, and aliphatic substrates). 

Scheme 44 Plausible pathway of Fe-catalyzed dehydration of primary amides to nitriles...

In the dehydration of primary aliphatic or aromatic amides to nitriles with CDI, the CDI is activated by an excess of a reactive halide, such as allyl bromide or benzyl bromide (2 equiv. of CDI, 8 equiv. of reactive halide, refluxing CH3CN, 2-5h) [12]... 

A series of N-substituted narceine amides (Section III,D,1) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the ( )-narceine imide (117) type (100). Similar transformations were performed in the hydrastine series (101). JV-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (Z)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5). 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

A Nylon recycle based on depolymerization via ammonolysis has been shown to be a technically feasible route for the recovery of high purity Nylon intermediates (1-6). In the ammonolysis process, the secondary amides of the Nylon (-6 and / or -6,6) fibers/polymers react with ammonia to break the Nylon chain and form a primary amide and an amine (Figure 1). The primary amide can subsequently be dehydrated to form a nitrile group. The net result is that the ammonolysis product is predominantly a mixture of four major components. 

Dehydration of amides.1 Primary amides are converted by this reagent into nitriles at 25° in 82-92% yield. Actually, this reaction occurs more readily than dehydration of a secondary hydroxyl group. 

Di-2-pyridyl sulphite (343) (from 2-pyridone and thionyl chloride in the presence of triethylamine) transforms primary aliphatic and aromatic amines RNH2 into N-sulphinylamines RN=S=0 and it dehydrates amides ArCONH2 to aryl cyanides, aldehyde oximes RCH=NOH (R = Cxlf 7. 4-MeOCgH4 or PhCH=CH) to the cyanides RCN and A-alkyl- and TV-ary Iformamides RNHCHO to isocyanides RNC. Aliphatic and aromatic... 

Thionyl chloride (SOCI2) has often been used as a dehydrating agent for primary, secondary, as well as tertiary p-hydroxy amides. With primary hydroxyl amides, the intermediate p-chloro amide can usually be isolated, which will then... 

Nitriles are most commonly prepared via the conversion of carboxylic acids to primary amides, followed by dehydration with boiling acetic anhydride, or other commonly employed dehydration reagents, e.g. SOCI2 or POCI3. This is a useful synthesis for amide, because it is not limited by steric hindrance. Alkyl nitriles can be prepared by the action of metal cyanides on alkyl halides (see Section 5.5.2). 

Many methods for the dehydration of primary amides to nitriles involve the use of strong acids and/or other reagents which are incompatible with sensitive functionality. French workers have recently described an unusual, mild, efficient (64-92%) and fairly general procedure for the RCONH2 —> RCN transformation which simply involves heating a mixture of the amide, an aldehyde and formic acid under reflux in acetonitrile for 12 hours. The following observations were made ... 

Chiral nitriles.2 This reagent is recommended for the dehydration in 60% yield of primary amides with an asymmetric center at the a-position to chiral nitriles with negligible racemization. The most satisfactory reagents for dehydration of optically active oximes to chiral nitriles is l,l -carbonyldiimidazole or N,N -tlicyclohexylcarbodiimide. 

---