Some Derivatives of Carboxylic Acids

Three important elasses of aeid derivatives are formed by the replacement of the hydroxyl group by another atom or group of atoms. Each of these derivatives contains an acyl group (outlined in red in the following general structure types). 

Aromatie eompounds of these types (with R = aryl groups) are also encormtered frequently. 

The acjd halides, sometimes ealled add halides, are stmeturally related to earboxylie aeids by the replacement of the — OH group by a halogen, most often — Cl. They are usually 

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Acid halides are very reactive and have not been observed in nature. 

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Aldehydes and Ketones 27-12 Amines 27-13 Carboxylic Acids 27-14 Some Derivatives of Carboxylic Acids 27-15 Summary of Functional Groups... 

What Are Some Derivatives of Carboxylic Acids, and How Are They Named ... 

There are some problems associated with the use of functional derivatives of carboxylic acids. Long-chain acid anhydrides are not commercially available, and one half of the acylation reagent is not utilized. Acyl chlorides require the use of tertiary base catalysts, whose double role has been explained before. Some of the intermediate acyl ammonium compounds formed are, however, insoluble in the solvent system. Examples include RCO - N+EtsCL in LiCl/DMAc, where RCO refers to the propionyl, hexanoyl, and stearoyl moiety, respectively. Hexanoyl- and stearoyl-pyridinium chlorides are also insoluble in the same solvent system [185]. 

Many of the common reagents for introducing nitrophenyl chromophores into a molecule for DV-visible detection are also suitable for use with the electrochemical detector [554,555,637]. Some further exeuaples aure the formation of p-aminophenyl derivatives of carboxylic acids [637], N-(4-anilinophenyl) aaleimide derivatives of sulfadiydryl compounds [639], and... 

It is particularly interesting, that some titanium and tantalum carbene complexes olefinate derivatives of carboxylic acids. These reagents are, moreover, much less basic than phosphorus ylides, and thus enable the olefination of strongly C-H acidic carbonyl compounds. 

Until a few years ago there was only indirect evidence for the existence of the species postulated as tetrahedral intermediates in reactions of derivatives of carboxylic acids (cf. Kirby, 1972). Now, however, it is possible to generate some of them in solution at sufficiently high concentrations for their uv and nmr spectra to be measured and for their reactions to be studied. It is the purpose of this review to record progress that has been made in this area. 

The familiar substitution reactions of derivatives of carboxylic acids with basic reagents illustrate nucleophihc substitution at aliphatic sp carbons. (Substitution reactions of carboxylic acids, and their derivatives, with acidic reagents are covered in Chapter 4.) The mechanisms of these reactions involve two steps (1) addition of the nucleophile to the carbonyl group and (2) elimination of some other group attached to that carbon. Common examples include the basic hydrolysis and aminolysis of acid chlorides, anhydrides, esters, and amides. 

Like other acid derivatives, acid chlorides typically undergo nucleophilic substitution. Chlorine is expelled as chloride ion or hydrogen chloride, and its place is taken by some other basic group. Because of the carbonyl group these reactions take place much more rapidly than the corresponding nucleophilic substitution reactions of the alkyl halides. Acid chlorides are the most reactive of the derivatives of carboxylic acids. 

How can we tell whether a dmg is likely to be susceptible to this type of degradation If the drug is a derivative of carboxylic acid or contains functional groups based on this moiety, for example an ester, amide, lactone, lactam, imide or carbamate (see Scheme 4.1), then we are dealing with a dmg which is liable to undergo hydrolytic degradation. We will consider some examples. 

Acid anhydrides as activated derivatives of carboxylic acids have found little attention for the preparation of acid halides. Their use can be justified if they are obtained from other sources than from carboxylic acids, e.g. phthalic anhydride from the oxidation of naphthalene or o-xylene. It is, therefore, no surprise that there exist patents to convert phthalic anhydride to phthalic acid dichloride with carbonyl dichloride in the presence of catalysts. " However, there are some methods available thus a,a-di-chloromethyl methyl ether will convert acid anhydrides to acid chlorides and brenzcatechyl phosphorus tribromide will also achieve this transformation. Fluorides may be prepared similarly with the pyridine/HF mixture of 01ah. °... 

Other derivatives of carboxylic acids and some unusual catalyst systems have found favor. Diarylboryl hexachloroantimonates activate acyl chlorides, carboxylic anhydrides and acyl enolates. A number of metal oxides have been successfully employed. It is worth noting at this point that the chloroacetylium and bromoacetylium ions, which can be prepared in either Freon 113 or sulfur dioxide, are more stable than the acetylium ion and have been shown to give high yields of ketones at low temperatures. ... 

Cyanoformamidines, exhibiting nucleophilic and electrophilic properties in the 1,3-positions, react with hexafluoroacetone forming five-membered heterocycles (86CB2127). This ability to form five-membered heterocycles is the major characteristic of hexafluoroacetone, which is also inherent in some perfluorinated and partially fluorinated ketones, aldehydes, and imines in their reactions with a-functional derivatives of carboxylic acids, as well as w-amino, a-N-alkylamino,... 

Formic acid is the irritant in the sting of certain ants. Vinegar is a 5 percent solution of acetic acid in water. Benzoic acid is used to synthesize aspirin. Carboxylic acids are found extensively in nature. The tartness of many fruits as well as sour milk is due to carboxylic acids. Some acids have very unpleasant odors. Derivatives of carboxylic acids are important in lipids (fats), synthetic plastics and fibers, aspirin, and soaps. 

The process of substitution undertaken on carboxylic acids and the derivatives of carboxylic acids (anhydrides, acid halides, esters, amides, and nitriles) generally involves a series of replacement processes. Thus, individually, substitution may involve replacement of (a) the proton attached to oxygen of the -OH group (i.e., ionization of the acid) (b) the hydroxyl (-OH) portion of the carboxylic acid (or derivative) (e.g., esterification) (c) the carbonyl oxygen and the hydroxyl (-OH) (e.g., orthoester formation, vide infra) (d) the entire carboxylic acid functionality (e.g., the Hunsdiecker reaction, already discussed Scheme 9.101) and the decarboxylation of orotic acid (as orotidine monophosphate) to uracil (as uridine monophosphate)—catalyzed by the enzyme orotidine monophosphate decarboxylase (Scheme 9.115) or (e) the protons (if any) on the carbon to which the carboxylic acid functional group is attached (e.g., the Dieckman cycUzation, already discussed earlier, c Equation 9.91). Indeed, processes already discussed (i.e., reduction and oxidation) have also accomplished some of these ends. Some additional substitutions for the carboxylic acid group itself are presented in Table 9.6, while other substitutions for derivatives of carboxylic acids are shown in Tables 9.7-9.10 and discussed subsequently. 

FIGURE 18.1 Some acyl and related derivatives of carboxylic acids. 

Nitriles, RC=N, are considered derivatives of carboxylic acids because the nitrile carbon is in the same oxidation state as the carboxy carbon and because nitriles are readily converted into other carboxylic acid derivatives. This section describes the rules for naming nitriles, the structure and bonding in the nitrile group, and some of its spectral characteristics. Then it compares the chemistry of the nitrile group with that of other carboxylic acid derivatives. 

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