Substituent carboxylic acids

Spectrum 5.5 shows the effect of a single deshielding substituent (carboxylic acid) on the benzene ring. 

Carbonyl groups are reduced selectively in the presence of many other substituents carboxylic acid, ester, nitrile, and nitro groups. In this rcspecl I he reagent exhibits selectivity comparable to sodium borohydride but should be useful when it is desirable to avoid alkaline conditions. 

Depending on the substituent carboxylic acids RCOOH may form rather complicated crystal structures 80,8l. The simplest carboxylic acids, formic and acetic acid, form catemeric chains in the... 

The presence of certain substituents e.g., the amino group) may markedly affect the solubibty and other properties of the sulphonic acid or carboxylic acid. Thus such sulphonic acids as the aminobenzenesul-phonic acids, pyridine- and quinoline-sulphonic acids exist in the form of inner salts or zwitter-ions that result from the interaction of the basic amino group and the acidic sulphonic acid. Sulphanilic acid, for example, is more accurately represented by formula (I) than by formula (II) ... 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

Two aldehydes two ketones or one aldehyde and one ketone may be formed Let s recall the classes of carbonyl compounds from Table 4 1 Aldehydes have at least one hydrogen on the carbonyl group ketones have two carbon substituents—alkyl groups for example—on the carbonyl Carboxylic acids have a hydroxyl substituent attached to the carbonyl group... 

Systematic names for carboxylic acids are derived by counting the number of car bons m the longest continuous chain that includes the carboxyl group and replacing the e ending of the corresponding alkane by oic acid The first three acids m Table 19 1 methanoic (1 carbon) ethanoic (2 carbons) and octadecanoic acid (18 carbons) illus trate this point When substituents are present their locations are identified by number... 

The effect of structure on acidity was introduced m Section 1 15 where we developed the generalization that electronegative substituents near an lomzable hydrogen increase Its acidity Substituent effects on the acidity of carboxylic acids have been extensively studied... 

An electronegative substituent particularly if it is attached to the a carbon increases the acidity of a carboxylic acid As the data m Table 19 2 show all the mono haloacetic acids are about 100 times more acidic than acetic acid Multiple halogen sub stitution increases the acidity even more trichloroacetic acid is 7000 times more acidic than acetic acid ... 

The enol content of a carboxylic acid is far less than that of an aldehyde or ketone and introduction of a halogen substituent at the a carbon atom requires a different set... 

Carboxylic acids are weak acids and m the absence of electron attracting substituents have s of approximately 5 Carboxylic acids are much stronger acids than alcohols because of the electron withdrawing power of the carbonyl group (inductive effect) and its ability to delocalize negative charge m the carboxylate anion (resonance effect)... 

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group Resonance m carboxylate anions is more effective than resonance m carboxylic acids acyl chlorides anhydrides thioesters esters and amides... 

Infrared IR spectroscopy is quite useful in identifying carboxylic acid derivatives The, carbonyl stretching vibration is very strong and its position is sensitive to the nature of IKT the carbonyl group In general electron donation from the substituent decreases the double bond character of the bond between carbon and oxygen and decreases the stretch mg frequency Two distinct absorptions are observed for the symmetric and antisym metric stretching vibrations of the anhydride function... 

The presence of the unsaturated substituent along this polyester backbone gives this polymer crosslinking possibilities through a secondary reaction of the double bond. These polymers are used in paints, varnishes, and lacquers, where the ultimate cross-linked product results from the oxidation of the double bond as the coating cures. A cross-linked polyester could also result from reaction (5.J) without the unsaturated carboxylic acid, but the latter would produce a gel in which the entire reaction mass solidified and is not as well suited to coatings applications as the polymer that crosslinks upon drying. ... 

Pyrrole Carboxylic Acids and Esters. The acids are considerably less stable than benzoic acid and often decarboxylate readily on heating. However, electron-withdrawing substituents tend to stabilize them toward decarboxylation. The pyrrole esters are important synthetically because they stabilize the ring and may also act as protecting groups. Thus, the esters can be utilized synthetically and then hydrolyzed to the acid, which can be decarboxylated by heating. Often P-esters are hydrolyzed more easily than the a-esters. 

Isoquinoline reacts with aliphatic carboxylic acids photolyticaHy or with a silver catalyst to give excellent yields of alkylation products by decarboxylation (155). This method is useful in the synthesis of 2-benzoyhsoquinolines bearing a variety of aromatic substituents in the 1-position (156). 

Some 4,5-disubstituted pyridazines exhibit ring-chain isomerism involving heterospiro compounds. For example, 5-(o-aminophenylcarbamoyl)pyridazine-4-carboxylic acid exists in a zwitterionic form in the solid state, but in a solution of DMSO it is almost exclusively 3, 4 -dihydro-3 -oxospiro[pyridazine-5(2//),2 (l //)-quinoxaline]-4-carboxylic acid (134). The equilibrium is strongly influenced by the nature of the solvent, the substituents on the pyridazine ring and the nucleophilicity of the group attached to the phenyl ring (Scheme 48) <80JCS(P2)1339). 

Methyl groups in pyridopyrazines (64IMC240) and pyridopyrazinones (71TH21500) are oxidized to carboxylic acids with potassium permanganate. Aryl carbinol substituents are also very readily oxidized to benzoyl derivatives in alkaline conditions (76CPB238). Bromina-tion of 2,3-dimethylpyrido[3,4-f ]pyridazine gives the 2,3-bisbromomethyl derivative, whilst... 

Most syntheses of this type have followed the classical Gould-Jacobs pattern (Section 2.15.5.4.2) in which 2-aminopyrazines bearing a 6-substituent give esters of 8-oxopyrido[2,3-f ]pyrazine-7-carboxylic acids (424) via the usual intermediate ethoxy-methylenemalonate adducts. In some cases the isomeric pyrazino[l,2-a]pyrimidines are formed in addition (e.g. 74CPB1864). 

Isothiazoles with electron-releasing substituents such as amino, hydroxy, or alkoxy in the 3- or 5-position are brominated in high yield in the 4-position. Alkylisothiazoles give lower yields, but 3-methylisothiazole-5-carboxylic acid has been brominated in 76% yield (72AHC(14)1). Again, thiazoles with an electron-releasing substituent in the 2- or 4-position are brominated at the 5-position (79HC(34-1)5). 

Potassium t-butoxide in t-butyl alcohol requires powerful electron-attracting substituents at C-4 to effect ring opening of pyrazoles but sodamide does not (Scheme 26) (B-76MI40402). As the key to the transformation is the generation of the anion, similar results were obtained by heating some pyrazole-3-carboxylic acids with quinoline. 

Both 1,2- and 2,1-benzisothiazoles react with electrophiles to give 5- and 7-substituted products (see Section 4.02.3.2). The isothiazole ring has little effect on the normal characteristics of the benzene ring. C-Linked substituents react almost wholly normally, the isothiazole ring having little effect except that phenyl substituents are deactivated (see Section 4.17.2.1). There are, however, considerable differences in the ease of decarboxylation of the carboxylic acids, the 4-isomer being the most stable (see Section 4.02.3.3). 

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