Benzoic acid 3,4-disubstituted

It occasionally happens that a reaction proceeds much faster or much slower than expected on the basis of electrical effects alone. In these cases, it can often be shown that steric effects are influencing the rate. For example, Table 9.2 lists relative rates for the Sn2 ethanolysis of certain alkyl halides (see p. 390). All these compounds are primary bromides the branching is on the second carbon, so that field-effect differences should be small. As Table 9.2 shows, the rate decreases with increasing P branching and reaches a very low value for neopentyl bromide. This reaction is known to involve an attack by the nucleophile from a position opposite to that of the bromine (see p. 390). The great decrease in rate can be attributed to steric hindrance, a sheer physical blockage to the attack of the nucleophile. Another example of steric hindrance is found in 2,6-disubstituted benzoic acids, which are difficult to esterify no matter what the resonance or field effects of the groups in the 2 or the 6 position. Similarly, once 2,6-disubstituted benzoic acids are esterified, the esters are difficult to hydrolyze. 

Astles PC, Brown TJ, Handscombe CM, Harper MF, Harris NV, Lewis RA, Lockey PM, McCarthy C, McLay IM, Porter B, Roach AG, Smith C, Walsh RJA. Selective endothelin A receptor antagonists. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives. Eur J Med Ghent 1997 32 409-23. 

An /n-geometry can be ensured by appropriate substitution of the building block which carries the acid-base functionality, for instance by using 2,6-disubstituted aromatic compounds like pyridines, 2,6-disubstituted benzoic acids or other 2,6-disubstituted phenyl derivatives (see Scheme 1). The use of 2,6-disubstituted arenes is sometimes called the 1,3-xylyl trick and assures an intra-annular orientation. 

So far, we have discussed monomacrocyclic intra-annular acids, but bimacrocyclic concave benzoic acids [74a]-[74c] and [75] have also been synthesized and their acidities determined at 25°C by photometric measurements in ethanol (Wangnick, 1991). Table 17 compares the (ethanol) values. No general trend could be found for the acidity of concave benzoic acids [74] and [75]. While [75] with 3,5-disubstituted outer phenyl rings was slightly more acidic than benzoic or acetic acid, [74] with 2,6-disubstituted outer phenyl rings was much less acidic than the non-macrocyclic analogues. 

In a series of ten morphine 3-benzoates, large differences in rates of enzymatic hydrolysis were seen [122], In 80% human plasma at pH 7.4 and 37°, the unsubstituted 3-benzoate had a tm value of 0.6 h, whereas esters of 2,6-disubstituted benzoic acid were much more resistant to enzymatic attack (t1/2 ranging from 60 h for the dimethylbenzoate to 300 h for the dichloro-and dimethoxybenzoates). Although these results point to marked steric hindrance, electronic effects cannot be excluded but escape characterization because of the limited series. Furthermore, and as mentioned repeatedly in this text, the possibility of binding to plasma proteins is a complicating factor that should be kept in mind. 

A structural requirement for the asymmetric Birch reduction-alkylation is that a substituent must be present at C(2) of the benzoyl moiety to desymmetrize the developing cyclohexa-1,4-diene ring (Scheme 4). However, for certain synthetic applications, it would be desirable to utilize benzoic acid itself. The chemistry of chiral benzamide 12 (X = SiMes) was investigated to provide access to non-racemic 4,4-disubstituted cyclohex-2-en-l-ones 33 (Scheme 8). 9 Alkylation of the enolate obtained from the Birch reduction of 12 (X = SiMes) gave cyclohexa-1,4-dienes 32a-d with diastereoselectivities greater than 100 1 These dienes were efficiently converted in three steps to the chiral cyclohexenones 33a-d. 

In this review, acids and bases [8] (benzoic acids, pyridines and 1,10-phenanthrolines) will be discussed as functional groups (light bulbs). They have been incorporated into bimacrocyclic structures by bis-a- or bis-orrlio-substitu-tion of the acids or bases 2,6-disubstituted benzoic acids and pyridines, and 2,9-disubstituted 1,10-phenanthrolines were used. For the construction of the lamp shade , attention had to be paid to the components. They had to be unreactive in order not to interfere with the reactive light bulbs . Therefore, for instance amine nitrogen atoms cannot be used as bridgeheads because they may act as bases. 

Kirsch et al. (1968) investigated the base-catalyzed hydrolysis of 24 meta- and para-disubstituted benzoic acid phenyl esters in acetonitrile/water (1 2) at 25°C ... 

For steric reasons the 2,6-disubstituted benzoic acids and esters are particularly susceptible to this type of cleavage reaction, and also particularly unreactive in the usual bimolecular solvolytic processes, and they have proved very convenient substrates for the study of the AacI mechanism. The kinetic work is discussed in a later section we are concerned at this point only with the qualitative behaviour of protonated esters amt acids, and of the structures of the cationic species. 

Difficulty Esterifiable Acids. The sterically hindered acids, such as 2.6-disubstituted benzoic acids, cannot usually be cslerified by conventional means. Several esters of sterically hindered acids such as 2,4.6-triisopropylbcnzoic acid have been prepared by dissolving 2 g of the acid in 14-20 mL of 100% H SOj. After standing a few minutes at room temperature, when presumably the acylium cation is formed, the solution is poured into an excess of cold absolute methanol. Most of the alcohol is removed under reduced pressure, about 50 ml. of water is added, and the distillation is continued under reduced pressure to remove the remainder of the methanol. The organic mailer is extracted with ether and treated with sodium carbonate solution. The ester is then distilled. Yields of esters made in this manner are 57-81%. 

Oxadiazoles have often attracted the attention of medicinal chemists as stable bioiso-steres of metabolically labile esters. 1,3,4-Oxadiazoles are generally prepared by cyclodehydration of 1,2-diacylhydrazines or their equivalents. Symmetrical 2,5-disubstituted examples were able to be rapidly prepared in a one-pot condensation-cyclodehydration of benzoic acids (2 equiv) with hydrazine dihydrochloride, in the presence of... 

Solvent effects on the dissociation of 11 2,6-disubstituted benzoic acids have been analysed by chemometric analysis.66 The acid-base behaviour of the three zwitterionic pyridinecarboxylic acids (picolinic, nicotinic, and isonicotinic acid) has been studied. The cationic form of picolinic acid converts partially into the corresponding zwitterion within a borderline acidity range (pH/acidity function). The various pXa values were determined for the three isomers by spectrophotometric and potentiometric methods and reasonable agreement was found.67... 

To further understand the mechanistic difference between aromatic substitution and the e reactions, reaction rate constants of disubstituted benzenes reacting with e were studied. Specifically, substituted benzoic acid was studied, and one substituent (-COOH) was kept constant. Table 12.6 lists the rate constants of substituted benzoic acid reacting with e. It also calculates r, which is defined as the following ... 

Despite the huge structural diversity of known carboxylic acids, most of these are readily converted into esters or amides. Even sterically hindered acids, for example pivalic, triphenylacetic [1], or 2,6-disubstituted benzoic acids [1, 2], can be converted into suitable acylating reagents for alcohols or amines (Scheme 7.1). Esters of sterically demanding carboxylic acids can, alternatively, also be prepared by O-alkylation of the corresponding carboxylates [3, 4]. 

Disubstituted isocoumarins are prepared from ortho-carboxy benzoic acids and a-diazophosphonates via a dirhodium(ll)-mediated O-H insertion followed by a Horner-Wadsworth-Emmons intramolecular cyclization (Scheme 210) <20020L2317>. 

Answer XILe is a disubstituted benzoic acid (3-bromo-5 methoxybenzoic acid). 

Formation of alternative hydrogen bonding patterns. Although less common than the R2(8) motif, carboxylic acids can adopt the C(4) motif. This has been shown to be important for sterically hindered 2,6-disubstituted benzoic acids... 

Khan et al. [28] synthesized the 2,5-disubstituted-l,3,4-oxadiazoles from 3-pyridyl hydrazide and benzoic acid by microwave irradiation taking alumina as the sohd support and phosphorus oxy chloride as a dehydrating agent. ... 

Figure 5.5. Absorption spectra of several monosubstituted and para-disubstituted benzenes10. 1, benzene 3, toluene 6, phenol 8, benzensulphonamide 23, p chlorophenol 11, benzoic acid 29, p-toluicacid anion 32, p-chloroaniline 38, p-hydroxybenzoic acid (1st) anion 41, p-hydroXybenzoic acid 56, p-hydroxybenzaldehyde 61, />-hydroxy-acetophenone anion 64, p-nitrophenol anion (Each unit on the ordinate axis represents ...

The or /io-positions of the benzene ring in 4,4-dimethyl-2-phenyl-4,5-dihydrooxazole 13, prepared from benzoyl chloride and the amino alcohol 12, are activated to such an extent that lithiation is possible. On reaction with an electrophile, e.g. a haloalkane, and followed by hydrolysis, 2-substituted or 2,6-disubstituted benzoic acids 14 or 15 are obtained [78] ... 

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