Aromatic acid amides hydrolysis

Nitrilase [EC 3.5.5.1], also known as nitrile aminohy-drolase and nitrile hydratase, catalyzes the hydrolysis of a nitrile to produce a carboxylate and ammonia. The enzyme acts on a wide range of aromatic nitriles. Nitrile hydratase [EC 4.2.1.84], also known as nitrilase, catalyzes the hydrolysis of a nitrile to produce an aliphatic amide. The enzyme acts on short-chain aliphatic nitriles, converting them into the corresponding acid amides. However, this particular enzyme does not further hydrolyze these amide products nor does the enzyme act on aromatic nitriles. 

N-Benzylamides are recommended when the corresponding acid is liquid and/or water-soluble so that it cannot itself serve as a derivative. The benzyl-amides derived from the simple fatty acids or their esters are not altogether satisfactory since they are often low melting those derived from most hydroxy acids and from polybasic acids or their esters are formed in good yield and are easily purified. The esters of aromatic acids yield satisfactory derivatives but the method must compete with the equally simple process of hydrolysis and precipitation of the free acid, an obvious derivative when the acid is a solid. The procedure fails with esters of keto acids, sulphonic acids and inorganic acids and some halogenated aliphatic esters. 

Substituted aromatic carboxylic acid amides of the type ArCONHR and Ar-CONR2 are only slowly attacked by aqueous alkali and are characterised by hydrolysis under acidic conditions 70 per cent sulphuric acid (prepared by carefully adding 4 parts of acid to 3 parts of water) is the preferred reagent. Use the general procedure which has been outlined on p. 1229 characterise the acidic and basic components. 

Introduction of RLi-unreactive silicon substituents has advantages in protection of Ar-C-H and Ar-CH3 sites. Thus taking advantage of the cooperativity of amide and methoxy DMG, metalation-silylation followed by metalation-E+ quench affords, after fluoride-mediated desilylation and amide hydrolysis, a route 1,2,5-substituted benzoic acids, 18 —> 19 (Scheme 5). Lateral metalation, of considerable utility in post-DoM chain extension [19], followed by double silyla-tion and further DoM-E+ quench and the same fluoride and acid treatment steps, furnishes 1,2,3,4-tetrasubstituted aromatic compounds, 20 —> 21 [10, 20],... 

Although the selfcondensation of amide chlorides proceeds well to give amide chlorides derived from 3-keto acids (56 equation 35) this reaction has only been used to synthesize 3-keto acid amides, which result after hydrolysis of the condensation products (56), and not to prepare the salts (56) in the pure state. The condensation reaction of aromatic aldehydes with the //A -dimethylacetamide-POCb adduct... 

The reagent can be used for introduction of a carboxyl group into an aromatic compound, for example a polystyrene resin. Friedel-Crafts acylation gives an amide, which on hydrolysis gives the aromatic acid. 

Amide hydrolysis is a key step in the widespread strategy of protection/deprotection of amino groups for synthetic purposes, usually carried out in homogeneous phase with mineral acids. It is shown here that under mild conditions (batch reactor, liquid phase, 75°C) large pore zeolites (HY, HBeta, HMOR) can catalyse the hydrolysis of various aromatic amides. The best results are obtained over HY zeolite samples with Si/Al ratios of 16 and 30 e.g. complete and selective hydrolysis of 2-nitroacetanilide after 2-4 hours reaction for a zeolite/substrate ratio of 0.5 g/mmol. For similar values of the Si/Al ratio HBeta and rather all HMOR samples are much less active than HY samples, which is probably related to diffusion limitations. 

Capsaicin and capsaicinoids undergo Phase I metabolic conversion involving both oxidative and non-oxidative paths. The liver is the major site of this enzymatic activity. Lee and Kumar (1980) demonstrated the conversion of catechol metabolites via hydroxylation of vanil-lyl ring. In rats, dihydrocapsaicin is metabolized to products that are excreted in the urine as glu-curonides (Kawada and Iwai, 1985). The generation of a quinone derivative occurs via O-demethylation at the aromatic ring with concomitant oxidation of the semiquinone and quinone derivatives or via demethylation of the phenoxy radical intermediate of capsaicin. Additionally, the alkyl side chain of capsaicin is also susceptible to oxidative deamination (Wehmeyer et al., 1990). There is evidence that capsaicinoids can undergo aliphatic oxidation (cu-oxidation) (Surh et al, 1995 Reilly et al, 2003) which is a possible detoxification pathway. Non-oxidative pathways are also involved in the bioconversion of capsaicin, e.g. hydrolysis of the acid-amide bond to yield vanillylamine and fatty acyl moieties (Kawada et al, 1984 Kawada and Iwai, 1985 Oi et al, 1992). 

Aromatic isocyanates react with regular olefins only in the presence of metal catalysts. For example, reaction of ethylene with phenyl isocyanate in the presence of liganded nickel (o) catalysts under argon in THF at -20 °C affords a five-membered ring metalla-cycle, which on hydrolysis gives a Af-substituted carboxylic acid amide. Heating of the metallacycle causes jS-elimination with formation of Af-substituted acrylic acid amides Diolefines and allenes also undergo this reaction with phenyl isocyanate. From 1,1-bis-p-dimethylaminophenylethylene and p-nitrophenyl isocyanate a linear 1 1 adduct is obtained... 

Should the chloride molecule contain certain groups which would cause the corresponding amide to have too high a melting point (nitro groups, halogens), an ester is prepared from the chloride by reaction with methanol or ethanol (see p. 252). Chlorides of aromatic acids yield solid acids on hydrolysis, which makes it possible simply to heat the tested substance with an aqueous solution of soda until dissolved and to precipitate the acid by acidification of the solution. 

Amides (except urea and thiourea), imides and nitriles, after the above alkaline hydrolysis, give derivatives similarly to those from the alkaline solution obtained from ammonium salts (p. 360). (A) If the original compound is aromatic, acidification of the cold solution deposits the crystalline acid. (B) The cold solution, when carefully neutralised (p. 332) and treated with benzylthiuronium chloride, deposits the thiuromum salt. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

The characterisation of a primary aromatic amide is based upon its own m.p. and the identification of the acid (see Section IV,175) produced on hydrolysis. A crystalline derivative may be prepared directly with xanthhydrol (for experimental details, see Section 111,110, 1). 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

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