Subject aromatic acids

Mixed condensations of esters are subject to the same general restrictions as outlined for mixed aldol reactions (Section 2.1.2). One reactant must act preferentially as the acceptor and another as the nucleophile for good yields to be obtained. Combinations that work best involve one ester that cannot form an enolate but is relatively reactive as an electrophile. Esters of aromatic acids, formic acid, and oxalic acid are especially useful. Some examples of mixed ester condensations are shown in Section C of Scheme 2.14. Entries 9 and 10 show diethyl oxalate as the acceptor, and aromatic esters function as acceptors in Entries 11 and 12. 

We have presented evidence that pyrrole-2-carboxylic acid decarboxylates in acid via the addition of water to the carboxyl group, rather than by direct formation of C02.73 This leads to the formation of the conjugate acid of carbonic acid, C(OH)3+, which rapidly dissociates into protonated water and carbon dioxide (Scheme 9). The pKA for protonation of the a-carbon acid of pyrrole is —3.8.74 Although this mechanism of decarboxylation is more complex than the typical dissociative mechanism generating carbon dioxide, the weak carbanion formed will be a poor nucleophile and will not be subject to internal return. However, this leads to a point of interest, in that an enzyme catalyzes the decarboxylation and carboxylation of pyrrole-2-carboxylic acid and pyrrole respectively.75 In the decarboxylation reaction, unlike the case of 2-ketoacids, the enzyme cannot access the potential catalysis available from preventing the internal return from a highly basic carbanion, which could be the reason that the rates of decarboxylation are more comparable to those in solution. Therefore, the enzyme cannot achieve further acceleration of decarboxylation. In the carboxylation of pyrrole, the absence of a reactive carbanion will also make the reaction more difficult however, in this case it occurs more readily than with other aromatic acid decarboxylases. 

JCS(P1)1433). Another interesting case of aromatization involves the formation of triazolethiones 184 by loss of phenylisonitrile from the fused-ring triazolines 114 in Scheme 38 when subjected to acid hydrolysis (84CCC1713). 

Aromatic Acids by Oxidation of Side Chains. German work on this subject is briefly reported on by Mittag (74, T J) and by Michel and Krey (7 ). 

These favourable results can probably be traced back to the stable chelates formed by the lithium salts of the aldol adducts. In the hydrolysis product the nitrogen of the aldimine group is linked through an intramolecular hydrogen bond bridge, as was established by the IR spectrum. Since the aldimine adduct could finally be converted by treatment with acid in a nearly quantitative yield to 3-phenylcinnamaldehyde, the preparative problem of subjecting aromatic ketones to the directed aldol condensation was solved. 

Based on these data, it is concluded that monoterpene esters will undergo in vivo hydrolysis in animals to yield the corresponding alcohols and carboxylic acids. Given that the carboxylesterases and lipases catalysing ester hydrolysis are present in all animals, including fish, it is concluded that monoterpene esters will be hydrolysed to yield monoterpene alcohols and simple aliphatic and aromatic acids. Once hydrolysed, the component alcohols and acids are subject to further oxidative metabolism and/or conjugation. 

Aryl halides are frequently prepared from the corresponding aryldiazonium salts by diazotation procedures. However, diazonium salts can be subjected directly to very mild Heck arylation conditions, which deliver coupled products (entry 19). Preferably, the reaction is executed in nonaqueous solvents such as acetonitrile, acetone, or methylene chloride with sodium acetate as base and with palladiumbis(dibenzylideneacetone) as catalyst. Alternatively, a combination of the amine and f-butyl nitrite, in a mixture of acetic acid and monochloroacetic acid, can provide the desired product directly, which makes the isolation of a diazonium salt unnecessary (entry 20). " It is also possible to use aromatic acid anhydrides as oxidative addition precursors (entry 21). Clearly, anhydrides are very interesting starting materials for a number of Heck reactions due to price and absence of halide salt formation. 

Successful mixed condensations of esters are subject to the same general restrictions as outlined in the consideration of mixed aldol condensations. One carbonyl compound must act preferentially as the acceptor and the other as the nucleophile. To compete with self-condensation of aliphatic esters, the carbonyl acceptor must be relatively electrophilic. The systems that have been commonly employed are esters of aromatic acids, formate esters, and oxalate esters. In each instance, these esters contain groups that are electron-withdrawing relative to alkyl and do not possess enolizable hydrogens. They are therefore good electrophiles, but cannot function as the nucleophile. Some examples are shown in Section C of Scheme 2.6. 

In a handful of cases, two CCXIH groups have been activated for the synthesis of biaryls. Larrosa and coworkers reported for the first time the decarboxylative homocoupling of aromatic acids mediated by Pd and Ag [62a]. The reaction makes use of Pd(TFA)j as a catalyst and Ag CO as an additive to afford the desired biaryls in 76-95% yields. The only by-products observed were due to the proto-decarboxylation of the aryl carboxylic acid. Both metals are essential for the reaction, and the role of the Ag salt is not only as the terminal oxidant but also as a mediator of the decarboxylation process. The method is subject to some limitations on the substituents on the benzoic acids. Thus, m- and p-nitrobenzoic acids as well as benzoic acids ortho substituted with F, Br, or MeO failed to give decarboxylative homocoupling products. In all cases, protodecarboxylations to the corresponding arenes were the main products observed. The same problem was reported in the protocol developed by Deng and coworkers, where the best results were obtained with PdCl and PPhj in the presence of Ag COj [62b]. 

COMPOUNDS SUBJECTED TO THE CURTIUS REACTION—CoMlmwed Aromatic Acid Derivativss—CorUinued... 

First, /7-coumaric acid is subjected to a j8-oxidation which reminds us of the j8-oxidation of the fatty acids and it is possible that the mechanism of the two reactions is the same. At any rate an aromatic acid is produced, the side chain of which is 2 C atoms shorter. It is called /7-hydroxybenzoic acid and is an example of a phenol carboxylic acid. In a completely analogous manner protocatechuic acid is obtained by j8-oxidation of caffeic acid, vanillic acid from ferulic acid, etc. 

Solvent extraction is subject to limitations imposed by the relatively unfavourable partition coefficients between aqueous solution and organic solvents that are shown by many organic acids. Diethyl ether alone will extract the most hydrophobic acids, whereas ethyl acetate improves the extraction of some of the more hydrophilic acids. The most suitable solvent can be selected by consideration of the acid or acids of interest [e.g. ether for phenyl-lactic acid, ethyl acetate for some other aromatic acids (Karoum et al, 1968)], although diethyl ether followed by ethyl acetate extraction, as employed by n any workers, provides a more comprehensive extraction system. Methyl acetate has been shown to increase the extraction of more hydrophilic acids such as citric acid (Lawson etal, 1976). 

Aromatic acids other than hippuric and 4-hydroxyphenylacetic acid and a few of exogenous (dietary) origin are generally observed in urine from normal subjects at very low levels, if at all, since those acids that occur in normal... 

Blau, K., Summer, G.K., Newsome, H.C., Edwards, C.H. andMamer, O.A. (1973), Phenylalanine loading and aromatic acid excretion in normal subjects and heterozygotes for phenylketonuria. Clin. Chim. Acta, 45,197. 

Metallic sodium. This metal is employed for the drying of ethers and of saturated and aromatic hydrocarbons. The bulk of the water should first be removed from the liquid or solution by a preliminary drying with anhydrous calcium chloride or magnesium sulphate. Sodium is most effective in the form of fine wire, which is forced directly into the liquid by means of a sodium press (see under Ether, Section II,47,i) a large surface is thus presented to the liquid. It cannot be used for any compound with which it reacts or which is affected by alkalis or is easily subject to reduction (due to the hydrogen evolved during the dehydration), viz., alcohols, acids, esters, organic halides, ketones, aldehydes, and some amines. 

Nitration in sulphuric acid is a reaction for which the nature and concentrations of the electrophile, the nitronium ion, are well established. In these solutions compounds reacting one or two orders of magnitude faster than benzene do so at the rate of encounter of the aromatic molecules and the nitronium ion ( 2.5). If there were a connection between selectivity and reactivity in electrophilic aromatic substitutions, then electrophiles such as those operating in mercuration and Friedel-Crafts alkylation should be subject to control by encounter at a lower threshold of substrate reactivity than in nitration this does not appear to occur. 

More information has appeared concerning the nature of the side reactions, such as acetoxylation, which occur when certain methylated aromatic hydrocarbons are treated with mixtures prepared from nitric acid and acetic anhydride. Blackstock, Fischer, Richards, Vaughan and Wright have provided excellent evidence in support of a suggested ( 5.3.5) addition-elimination route towards 3,4-dimethylphenyl acetate in the reaction of o-xylene. Two intermediates were isolated, both of which gave rise to 3,4-dimethylphenyl acetate in aqueous acidic media and when subjected to vapour phase chromatography. One was positively identified, by ultraviolet, infra-red, n.m.r., and mass spectrometric studies, as the compound (l). The other was less stable and less well identified, but could be (ll). 

Analytical and Test Methods. o-Nitrotoluene can be analyzed for purity and isomer content by infrared spectroscopy with an accuracy of about 1%. -Nitrotoluene content can be estimated by the decomposition of the isomeric toluene diazonium chlorides because the ortho and meta isomers decompose more readily than the para isomer. A colorimetric method for determining the content of the various isomers is based on the color which forms when the mononitrotoluenes are dissolved in sulfuric acid (45). From the absorption of the sulfuric acid solution at 436 and 305 nm, the ortho and para isomer content can be deterrnined, and the meta isomer can be obtained by difference. However, this and other colorimetric methods are subject to possible interferences from other aromatic nitro compounds. A titrimetric method, based on the reduction of the nitro group with titanium(III) sulfate or chloride, can be used to determine mononitrotoluenes (32). Chromatographic methods, eg, gas chromatography or high pressure Hquid chromatography, are well suited for the deterrnination of mononitrotoluenes as well as its individual isomers. Freezing points are used commonly as indicators of purity of the various isomers. 

Sulfonic acids may be subjected to a variety of transformation conditions, as shown in Figure 2. Sulfonic acids can be used to produce sulfonic anhydrides by treatment with a dehydrating agent, such as thionyl chloride [7719-09-7J. This transformation is also accomphshed using phosphoms pentoxide [1314-56-3J. Sulfonic anhydrides, particulady aromatic sulfonic anhydrides, are often produced in situ during sulfonation with sulfur trioxide. Under dehydrating conditions, sulfonic acids react with substituted aromatic compounds to give sulfone derivatives. 

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