Hydrolysis to amides

B). Many nitriles when treated with hydrogen peroxide in warm alkaline solution undergo hydrolysis to amides which can thus be readily obtained in high yield. Insoluble liquid nitriles can be treated directly in the aqueous suspension, but for insoluble solid nitriles the addition of a suitable organic solvent to give a complete solution may be desirable, although the completion of the hydrolysis may not then be so readily detected. 

All such nitriles appear to have been made by primary synthesis (see Chapter 15) or by the Reissert reaction (see Section 16.1.3) their only reported reaction involves hydrolysis to amides (see Section 21.3). 

Reactions of Nitriles Nitriles undergo acidic or basic hydrolysis to amides, which may be further hydrolyzed to carboxylic acids. Reduction of a nitrile by lithium aluminum hydride gives a primary amine, and the reaction with a Grignard reagent gives an imine that hydrolyzes to a ketone. 

Nitrile hydrolysis to amide is relatively facile subsequent hydrolysis to the acid requires somewhat more forcing conditions. 

Hydrolysis of Acetonitrile. Nitriles, like acid amides, undergo hydrolysis to give the corresponding carboxylic acid and ammonia. Consequently... 

The industrial process for preparing the reagent usually permits a little hydrolysis to occur, and the product may contain a little free calcium hydroxide or basic chloride. It cannot therefore be employed for drying acids or acidic liquids. Calcium chloride combines with alcohols, phenols, amines, amino-acids, amides, ketones, and some aldehydes and esters, and thus cannot be used with these classes of compounds. 

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... 

Acyl hahdes may be identified by —hydrolysis to the corresponding acids (the latter may be further characterised as in Section IV,175) conversion into amides (Section IV,191), anihdes or p-toluidides (Section IV,100) and conversion into sohd esters (Section IV,183). 

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetie acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3 dimethylaminomethylindole or gramine (II). The latter reaets in hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleaeet-amide (IV), part of which is further hydrolysed to 3-indoleacetic acid (V, as sodium salt). The product is a readily separable mixture of 20 per cent, of (IV) and 80 per cent, of (V). 

This difference m reactivity especially toward hydrolysis has an important result We 11 see m Chapter 27 that the structure and function of proteins are critical to life Itself The bonds mainly responsible for the structure of proteins are amide bonds which are about 100 times more stable to hydrolysis than ester bonds These amide bonds are stable enough to maintain the structural integrity of proteins m an aqueous environment but susceptible enough to hydrolysis to be broken when the occasion demands... 

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

We already discussed bolh Ihe acidic and basic hydrolysis of amides (see Seclion 20 17) All lhal remains to complete Ihe mechamslic piclure of nilrile hydrolysis is to examine Ihe conversion of Ihe nilnle to Ihe conespondmg amide... 

Adiponitrile undergoes the typical nitrile reactions, eg, hydrolysis to adipamide and adipic acid and alcoholysis to substituted amides and esters. The most important industrial reaction is the catalytic hydrogenation to hexamethylenediarnine. A variety of catalysts are used for this reduction including cobalt—nickel (46), cobalt manganese (47), cobalt boride (48), copper cobalt (49), and iron oxide (50), and Raney nickel (51). An extensive review on the hydrogenation of nitriles has been recendy pubUshed (10). 

Alitame (trade name Adame) is a water-soluble, crystalline powder of high sweetness potency (2000X, 10% sucrose solution sweetness equivalence). The sweet taste is clean, and the time—intensity profile is similar to that of aspartame. Because it is a stericaHy hindered amide rather than an ester, ahtame is expected to be more stable than aspartame. At pH 2 to 4, the half-life of aUtame in solution is reported to be twice that of aspartame. The main decomposition pathways (Fig. 6) include conversion to the unsweet P-aspartic isomer (17) and hydrolysis to aspartic acid and alanine amide (96). No cyclization to diketopiperazine or hydrolysis of the alanine amide bond has been reported. AUtame-sweetened beverages, particularly colas, that have a pH below 4.0 can develop an off-flavor which can be avoided or minimized by the addition of edetic acid (EDTA) [60-00-4] (97). 

In the case of nicotinamide, the color yield is often low. This problem can be circumvented by either hydrolysis to nicotinic acid or by conversion of the amide to a fluorescent compound. Treatment of nicotinamide with methyl iodide yields the quaternary ammonium salt, /V-methyl nicotinamide (5). Reaction of this compound with acetophenone yields a fluorescent adduct (49). Other carbonyl compounds have also been used (50—54). 

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

Nitrile Group. Hydrolysis of the nitrile group proceeds through the amide to the corresponding carboxyUc acid. Because cyanohydrins are unstable at high pH, this hydrolysis must be cataly2ed by acids. In cases where amide hydrolysis is slower than nitrile hydrolysis, the amide may be isolated. 

Pyrimido[4,5- f]pyrimidines may be used as pyrimidine precursors. Thus, the dihydro derivative (736) undergoes alkaline hydrolysis to the amide (737 R = PrCO) which may be deacylated in ethanolic hydrogen chloride to give 5-aminomethyl-2-propylpyrimidin-4-amine (737 R = H) (64CPB393) rather similarly, the pyrimidopyrimidinedione (738) reacts with amines to give, for example, 6-amino-5-benzyliminomethyl-l,3-dimethylpyrimidine-2,4(lFf,3Ff)-dione (739 R = CH2Ph) or the hydrazone (739 R = NH2) (74JCS(Pl)1812). 

Esters undergo hydrolysis and conversion to amides under the usual conditions, and amide side chains have also been formed from the acid and amine with DCCI. Acids have been formed from the corresponding spirohydantoins via ureido derivatives (Section 2.15.15.6.1), and undergo decarboxylation in the usual manner. 

The hydrolysis of amides to carboxylic acids and amines requires considerably more vigorous conditions than ester hydrolysis. The reason is that the electron-releasing... 

The mechanism for acid-catalyzed hydrolysis of amides involves attack by water on the protonated amide. An inqjortant feature of the chemistry of amides is that the most basic site in an amide is the carbonyl oxygen. Very little of the N-protonated form is present. The major factor that contributes to the stability of the O-protonated form is the... 

Nitriles are classified as carboxylic acid derivatives because they are converted to carboxylic acids on hydrolysis. The conditions required are similar- to those for the hydrolysis of amides, namely, heating in aqueous acid or base for several hours. Like the hydrolysis of amides, nitrile hydrolysis is ineversible in the presence of acids or bases. Acid hydrolysis yields fflnmonium ion and a carboxylic acid. 

The reaction of iminium salts such as 66 with salts of trichloroacetic acid has been shown to yield amides such as 84 on hydrolysis 126). It was suggested that the reaction proceeds by addition of dichlorocarbene to give an aziridinium intermediate (85), which was opened by trichloroacetate followed by hydrolysis to give the observed products 126). The observed products from the reaction can be accounted for by formation of CCI3,... 

---