Carboxylic acid derivative polarity

Bile acids, which exist mainly as bile salts, are polar carboxylic acid derivatives of cholesterol that are important in the digestion of food, especially the solubilization of ingested fats. The Na and salts of glycocholic acid and tauro-cholic acid are the principal bile salts (Ligure 25.41). Glycocholate and tauro-cholate are conjugates of cholic acid with glycine and taurine, respectively. 

Carboxylic acid derivatives, CH3C(=0)Z, are similar to aldehydes and ketones in that they contain a polar carbonyl group. Therefore, nucleophiles should add to the carbonyl carbon, although the rate of addition may depend on the Z group. 

The addition of a nucleophile to a polar C=0 bond is the key step in thre< of the four major carbonyl-group reactions. We saw in Chapter 19 that when. nucleophile adds to an aldehyde or ketone, the initially formed tetrahedra intermediate either can be protonated to yield an alcohol or can eliminate th< carbonyl oxygen, leading to a new C=Nu bond. When a nucleophile adds to carboxylic acid derivative, however, a different reaction course is followed. Tin initially formed tetrahedral intermediate eliminates one of the two substituent originally bonded to the carbonyl carbon, leading to a net nucleophilic acy substitution reaction (Figure 21.1. ... 

A carboxylate derivative of a fully aromatic, water-soluble, hyperbranched polyphenylene is considered as a unimolecular micelle due to its ability to complex and solubilize non-polar guest molecules [23]. The carboxylic acid derivative of hyperbranched polyphenylene polymer (HBP) (My,=5750-7077, Mn=3810-3910) consists of 40-60 phenyl units that branch outward from a central point forming a roughly spherical molecule with carboxylates on the outer surface. The free acid form of HBP was suspended in distilled water and dissolved by adding a minimum quantity of NaOH. The solution was adjusted to pH 6.2 with aqueous HCl. Calcium carbonate crystals were growth from supersaturated calcium hydrogencarbonate solution at room temperature. HBP gave... 

The most significant change in these reactions is the formation of the carbon-nncleophile bond so, in both types of mechanism, the reaction is termed a nucleophilic addition. It should be noted that the polarization in the carbonyl group leads to nucleophilic addition, whereas the lack of polarization in the C=C donble bond of an alkene leads to electrophilic addition reactions (see Chapter 8). Carbonyl groups in carboxylic acid derivatives undergo a similar type of reactivity to nucleophiles, but the... 

The reaction involves the transfer of an electron from the alkali metal to naphthalene. The radical nature of the anion-radical has been established from electron spin resonance spectroscopy and the carbanion nature by their reaction with carbon dioxide to form the carboxylic acid derivative. The equilibrium in Eq. 5-65 depends on the electron affinity of the hydrocarbon and the donor properties of the solvent. Biphenyl is less useful than naphthalene since its equilibrium is far less toward the anion-radical than for naphthalene. Anthracene is also less useful even though it easily forms the anion-radical. The anthracene anion-radical is too stable to initiate polymerization. Polar solvents are needed to stabilize the anion-radical, primarily via solvation of the cation. Sodium naphthalene is formed quantitatively in tetrahy-drofuran (THF), but dilution with hydrocarbons results in precipitation of sodium and regeneration of naphthalene. For the less electropositive alkaline-earth metals, an even more polar solent than THF [e.g., hexamethylphosphoramide (HMPA)] is needed. 

The polarity alternation rule (PAR) considers two kinds of substituents. The donors are. those having unshared electronic pairs or -electrons, and +1 groups. These include OH, OR, OCOR, NH2, NRR, N(R)COR, SH, SR, halogens and alkyl groups. The donor properties of the alkyl groups may reflect the existence of hyperconjugation. On the other hand, the acceptors are electron sinks, i.e. polarizable it-bonds, atoms with empty orbitals, and —I groups. Examples of acceptors are C=0 (aldehydes, ketones, carboxylic acid derivatives), CN, S02, N02, SiRj. 

Due to the pharmaceutical importance of their reaction products, a number of fluorinated 4-oxo-l,4-dihydroquinoline-3-carboxylic acid derivatives have been treated with various thiols (Table 8). The displacement of fluorine proceeds under moderate conditions regiosclcctively at C-7 or C5 giving 2 or 3, respectively in the ease of the 5,6,7,8-tetrafluoro derivative, fluorine is replaced at C5 in a nonpolar solvent, e.g. toluene, and at C7 in polar solvents, e.g. ethanol.18... 

This procedure offers a convenient method for the esterification of carboxylic acids with alcohols2 and thiols2 under mild conditions. Its success depends on the high efficiency of 4-dialkylaminopyridines as nucleophilic catalysts 1n group transfer reactions. The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacidic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols, including polyols,2 6 a-hydroxycarboxylic acid esters,7 and even very acid labile... 

In all of these reactions, a nucleophile adds to a positively polarized carbonyl carbon to form a tetrahedral intermediate. There are three possible fates for the tetrahedral intermediate (1) The intermediate can be protonated, as occurs in Grignard reactions, reductions, and cyanohydrin formation. (2) The intermediate can lose water (or OH), as happens in imine and enamine formation. (3) The intermediate can lose a leaving group, as occurs in most reactions of carboxylic acid derivatives. 

Hlectronically, we find that strongly polarized acyl compounds react more readily than less polar ones. I hus, add chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic acid derivatives indicate the differences by the relative blueness on the C=0 carbons. Acyl phosphates are hard to place on this scale because they are not used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. 

The boiling points and melting points of other carboxylic acid derivatives are similar to those of other polar compounds of comparable size and shape. 

Carboxylic acid derivatives having > 5 C s are H2O insoluble because the nonpolar alkyl portion is too large to dissolve in the polar H2O solvent. 

The chemistry of carboxylic acid derivatives is dominated by the nucleophilic acyl substitution reaction. Mechanistically, these substitutions] take place by addition of a nucleophile to the polar carbonyl group of the acid derivative, followed by expulsion of a leaving group from the tetrahedral intermediate. 

Many oxidative processes (e.g., benzylic, allylic, alicyclic, or aliphatic hydroxylation) generate alcohol or carbinol metabolites as intermediate products. If not conjugated, these alcohol products are further oxidized to aldehydes (if primary alcohols) or to ketones (if secondary alcohols). Aldehyde metabolites resulting from oxidation of primary alcohols or from oxidative deamination of primary aliphatic amines often undergo facile oxidation to generate polar carboxylic acid derivatives." As a general rale, primary alcoholic groups and aldehyde functionalities are quite vulnera-... 

A related strategy was suggested in which one of the reactants is attached via a linker to tetrabenzo[a,c,g,i]fluorene (Tbf). The reaction product can now be purified by taking advantage of the high affinity of Tbf to charcoal in polar solvents (mixture of DCM and methanol). Desorption can be affected with non polar solvents such as toluene [144]. The method was exemplified by the synthesis of a quinolone carboxylic acid derivative (ciprofloxacin). 

Acid chlorides are noxious, irritating chemicals and must be handled with great care. They are slightly polar and boil at approximately the same temperature as the corresponding aldehyde or ketone of comparable molecular weight. They react violently with water and therefore cannot be dissolved in that solvent. Acid chlorides have little commercial value other than their utility in the synthesis of esters and amides, two of the other carboxylic acid derivatives. 

At this point we want to consider the relative reactivity of carboxylic acid derivatives and other carbonyl compounds in general terms. We return to the subject in more detail in Chapter 7. Let us first examine some of the salient structural features of the carbonyl compounds. The strong polarity of the C=0 bond is the origin of its reactivity toward nucleophiles. The bond dipole of the C-X bond would be expected increase carbonyl reactivity as the group X becomes more electronegative. There is another powerful effect exerted by the group X, which is resonance electron donation. 

Thioamides have become a ubiquitous but important class of compounds - much like ordinary organic compounds such as aldehydes, ketones, and carboxylic acid derivatives - and extensive studies into their syntheses and reactions have been carried out in recent years. When an oxygen atom in an amide is replaced with a sulfur atom, the compounds become less polar and more soluble in various organic solvents. They are reactive but still stable enough to be handled in air. Therefore, a tremendous number of studies have been made into their fundamental properties, biological aspects, and broad applicabilities. Theoretical studies into the rotational barriers that exist in the thioformamides 4 and the thioacetamides 5 have also been made (for example [1]). 

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