Aromatic acids from amides

N-oxidation can occur in a number of ways to give either hydroxylamines from primary and secondary amines [Eqs. (11) and (12)], hydroxamic acids from amides, or N-oxides from tertiary amines [Eq. (13)]. The enzyme systems involved are either cytochrome P450 or a flavoprotein oxygenase. Hydroxylamines may be further oxidized to a nitro compound via a nitroso intermediate [Eq. (11)]. Oximes can be formed by rearrangement of the nitroso intermediate or N-hydroxylation of an imine, that could in turn be derived by dehydration of a hydroxylamine [Eq. (11)]. N-Oxides may be formed from both tertiary arylamines and alkylamines and from nitrogen in heterocyclic aromatic systems, such as a pyridine ring. 

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 ... 

As a dibasic acid, malic acid forms the usual salts, esters, amides, and acyl chlorides. Monoesters can be prepared easily by refluxing malic acid, an alcohol, and boron trifluoride as a catalyst (9). With polyhydric alcohols and polycarboxyUc aromatic acids, malic acid yields alkyd polyester resins (10) (see Alcohols, polyhydric Alkyd resins). Complete esterification results from the reaction of the diester of maUc acid with an acid chloride, eg, acetyl or stearoyl chloride (11). 

Other Applications. Hydroxylamine-O-sulfonic acid [2950-43-8] h.2is many applications in the area of organic synthesis. The use of this material for organic transformations has been thoroughly reviewed (125,126). The preparation of the acid involves the reaction of hydroxjlamine [5470-11-1] with oleum in the presence of ammonium sulfate [7783-20-2] (127). The acid has found appHcation in the preparation of hydra2ines from amines, aUphatic amines from activated methylene compounds, aromatic amines from activated aromatic compounds, amides from esters, and oximes. It is also an important reagent in reductive deamination and specialty nitrile production. 

Tetrahydroharman, m.p. 179-80°, has been prepared by a number of workers by a modification of this reaction, viz., by the interaction of tryptamine (3-)5-aminoethylindole) with acetaldehyde or paraldehyde and Hahn et al. have obtained a series of derivatives of tetrahydronorharman by the use of other aldehydes and a-ketonic acids under biological conditions of pH and temperature, while Asahina and Osada, by the action of aromatic acid chlorides on the same amine, have prepared a series of amides from which the corresponding substituted dihydronorharmans have been made by effecting ring closure with phosphorus pentoxide in xylene solution. 

The palladium-catalyzed carbonylation of aryl halides in the presence of various nucleophiles is a convenient method for synthesizing various aromatic carbonyl compounds (e.g., acids, esters, amides, thioesters, aldehydes, and ketones). Aromatic acids bearing different aromatic fragments and having various substituents on the benzene ring have been prepared from aryl iodides at room temperature under 1 atm... 

As to the origins of the major N compounds identified, it is possible that at least a portion of some of these compounds are pyrolysis products of amino acids, peptides, proteins, [18] and porphyrins (a component of chlorophyll), [19] or originate from the microbial decomposition of plant lignins and other phenolics in the presence of ammonia. [20] Of considerable interest are the identifications aromatic and aliphatic nitriles. Nitriles can be formed from amines with the loss of 2 H2, from amides with the loss of H20, and also by reacting n-alkanoic acid with NH3. [21] The detection of long-chain alkyl- and dialkyl-nitriles points to the presence in the soil or SOM of long-chain amines... 

In the following sections, we discuss compounds whose amide group is adjacent to an aromatic system. A distinction is made between aromatic amides derived from aromatic acids (e.g., benzamides) or from aromatic amines (e.g., anilides). The discussion will be completed with compounds in which the amide bond links two aromatic systems. 

Comparison of IR spectra of humic acids from terrestriai soiis (A-C) and marine sediments (D-G). identification of iR bands (1) aiiphatic C-H (2) C=0 (3 and 5) amides (4) aromatic C=C and (6) C-0 in poiysaccharides. Source-. From Hue, A. Y, et al. (1974). Caracterisation Des Acides Humiques de Sediments Marins Recents et Comparaison avec ieurs Homoiogues Terrestres, Buiietin de L ENSAiA De Nancy, 16, 59-75. 

The basic components in the structure of local anesthetics are the lipophilic aromatic portion (a benzene ring), an intermediate chain, and the hydrophilic amine portion (Fig. 27.1). The intermediate chain has either an ester linkage from the combination of an aromatic acid and an amino alcohol or an amide linkage from the combination of an aromatic amine and an amino acid. The commonly used local anesthetics can be classified as esters or amides based on the structure of this intermediate chain. 

In a related vein, one of the benzene rings in dibenzepin (36-7) can be replaced by pyridine. In a one-pot reaction, condensation of the 2-chloronicotinic acid (43-2) with ortho-phenylenediamine (43-1) leads to the lactam (43-3). The order in which the two steps, aromatic displacement and amide formation, take place has not been elucidated. Simple alkylation of the anion from the product with 3-chloro-2-(AA -drmethylamino)propane (43-4) affords the antidepressant agent propizepine (43-5) [43]. 

Aromatic amides, sometimes referred to as aryiamides, exhibit the same relationship. Note the relationship of benzoic acid Cg H5 COOH with benzamide Q H5 CONH2. Thiamides are derived from amides in which there is substitution of the O atom by a sulfur atom. Thus, acetamide NHa- CO- CH3, becomes thiacetamide NH2- CS- CH3 or acetanilide C6 H5- NH- CO- CH3 becomes thiacetanilide C6 H5- NH- CS- CH3. Sulfonamides arc derived from the sulfonic acids. Thus, bcnzcnc-sulfonic acid Cg H5 SO2- OH becomes benzene-sulfonamide Cg Hs- SOv NH2. See also Sulfonamide Drugs. 

Other Applications. Hydroxylainine-O-sulfonic acid has many applications in the area of organic synthesis. The acid has found application in the preparation of hydrazines from amines, aliphatic amines from activated methylene compounds, aromatic amines from activated aromatic compounds, amides from esters, and oximes. 

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

Although there is not a direct simultaneous consumption of the base, even this possibility was admitted, assuming that alkylation of the amide group by the ester may occur (23). This seems however not to be correct, as the alkylation of amides produced by esters is limited to esters of aromatic acids only (73). Nevertheless, the esters might be accounted for a loss of basicity from the point of view of condensation reactions producing water and acidic products. 

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. 

A mixture of 50 per cent sulphuric acid and glacial acetic acid may be used with advantage in the case of diflicultly-hydrolysable aromatic nitriles. The reaction product is poured into water, and the organic acid is separated from any unchanged nitrile or from amide by means of sodium carbonate solution. 

Reactions between a representative range of alkyl- and aryl-amines and of aliphatic and aromatic acids showed that the direct formation of amides from primary amines and carboxylic acids without catalyst occurs under relatively low-temperature conditions (Scheme 1). The best result obtained was a 60% yield of N-bcnzyl-4-phenylbutan-amide from benzylamine and 4-phenylbutanoic acid. For all these reactions, an anhydride intermediate was proposed. Boric and boronic acid-based catalysts improved the reaction, especially for the less reactive aromatic acids, and initial results indicated that bifunctional catalysts showed even greater potential. Again, anhydride intermediates were proposed, in these cases mixed anhydrides of carboxylic acids and arylboronic acids, e.g. (I).1... 

Enzymes are made from just 20 a-amino acid building blocks (structures and abbreviations are shown in Table 5.1). Each amino acid has a unique side chain, or residue, which can be polar, aliphatic, aromatic, acidic, or basic. The amide bonds (peptide bonds) make up the enzyme s backbone, and the residues determine the ultimate structure and catalytic activity of the enzyme. When the sequence of amino acids (the primary structure) for an enzyme is assembled in vivo, it folds... 

The aromatic acid is available and we need consider only the pyrazole (core pyrazole ring in black in the diagram). The aromatic amino group can be put in by nitration and reduction and the amide can be made from the corresponding ester. This leaves a carbon skeleton, which must be made by ring synthesis. 

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