Carboxylic Acids and Related Derivatives

As already shown for dihydrothiazole-containing cyclic peptides (Section 6.8.5.2.2.2), basically two different synthetic routes are used for the introduction of dihydrooxazoles into cyclic peptides. In the first one, 2-(aminoalkyl)dihydrooxazole-4-carboxylic acids and related derivatives are synthesized,t554 571,572 589 590 then incorporated directly into the linear precursors, which are finally cyclized by standard protocols.1541.554.567.569.5711 Again the main disadvantage to this synthetic approach is the facile racemization of the dihydrooxazole syn-thon. Therefore, the preferred method is the production of the oxazolidine ring in the preassembled cyclic peptide. For this purpose various methods have been proposed. 

Synthesis of Pyrazolidine-3-carboxylic Acid and Related Derivatives... 

Oxo- (Hydroxy-) and Alkoxypurines 7 Thioxo- and Selenoxopurines and Derivatives 8 The Amino- (and Amino-oxo)purines 9 The Purine Carboxylic Acids and Related Derivatives 10 Nitro-, Nitroso-, and Arylazopurines 11 Purine N-Oxides Ch. 12 The Reduced Purines... 

Ultraviolet spectmm of carboxylic acids and related derivatives also had been studied. Their ultraviolet absorption characteristics can be given as follows ... 

In Chapter 9 you see the basic structure of each of the carboxylic acids and Ccirboxylic acid derivatives. In this chapter we focus on the carboxylic acids and related compounds, such as esters, acyl chlorides, and acid anhydrides, and we also include some information on amides (see Chapter 13 for an additional examination of cimides). Before you can get into synthesis and reactions, though, you need to understand the structure and nomenclature of these compounds. 

The following discussion deals not only with this reaction, but related reactions in which a transition metal complex achieves the addition of carbon monoxide to an alkene or alkyne to yield carboxylic acids and their derivatives. These reactions take place either by the insertion of an alkene (or alkyne) into a metal-hydride bond (equation 1) or into a metal-carboxylate bond (equation 2) as the initial key step. Subsequent steps include carbonyl insertion reactions, metal-acyl hydrogenolysis or solvolysis and metal-carbon bond protonolysis. 

A variety of 1,3-dicationic carboxonium superelectrophiles have been generated from protonation of carboxylic acids and their derivatives. For example, carboxonium-carbenium dications have been proposed in the superacid promoted reaction of cinnamic acid (50) and related... 

Chapter 22 continues the study of carbonyl compounds with a detailed look at nucleophilic acyl substitution, a key reaction of carboxylic acids and their derivatives. Substitution at sp hybridized carbon atoms was introduced in Chapter 20 with reactions involving carbon and hydrogen nucleophiles. In Chapter 22, we learn that nucleophilic acyl substitution is a general reaction that occurs with a variety of heteroatomic nucleophiles. This reaction allows the conversion of one carboxylic acid derivative into another. Every reaction in Chapter 22 that begins with a carbonyl compound involves nucleophilic substitution. Chapter 22 also discusses the properties and chemical reactions of nitriles, compounds that contain a carbon-nitrogen triple bond. Nitriles are in the same carbon oxidation state as carboxylic acids, and they undergo reactions that form related products. 

Carboxylic acids and their derivatives, esters, amides, anhydrides, and acyl halides, are formally synthesized from olefins, carbon monoxide, and compounds represented with HX where X- equals OR-, NR2-, etc (see Scheme 1). Considering that the chiral aldehydes obtained by asymmetric hydroformylation of viny-larenes are often oxidized in order to exhibit biological activities, asymmetric hydrocarboxylation and its related reactions naturally attract much attention. Unfortunately, however, as yet only less successful work has been reported on this subject than on hydroformylation. Palladium(II) is most commonly used for this purpose. Asymmetric hydrocarboxylation of olefins was first reported in 1973 by Pino using PdCl2 and (-)-DIOP [105]. Chiusoh reached 52% ee in the... 

In this sense, therefore, it is related to carboxylic acids and their derivatives. I hc importance of nitriles in. synthesis derives from the fact that the nitrile carbon may be introduced into a molecule as the nucleophilic cyanide ion in an S s2 reaction. Then, by the reactions in this text section, the nitrile may be converted to carboxylic acid derivatives, ketones, or aldehydes, in which the originally nucleophilic cyanide carbon has become an electrophilic carbonyl carbon. This is a good way to use a nucleophilic substitution to introduce a carbonyl carbon into a molecule. 

Concerning carboxylic acids and their derivatives, transformations of practical value are restricted to oxidative hydrolysis such as the conversion of hydrazides back to carboxylic acids, transamidation of iV-acyl-5,6-dihydrophenanthridines, and decarboxylative processes, especially the degradation of a-hydro-xymalonic acids (eq 9). In some cases the Ce oxidation is much superior to periodate cleavage. A related reaction is involved in a route to lactones. ... 

L-Azetidine-2-carboxylic Acid and Related Amino Acids Nonprotein Amino Acids Derived from Isoleucine L-Hypoglycin A and B... 

The reactions of carboxylic acids and their derivatives are summarized here. Many (but not all) of the reactions in this summary are acyl substitution reactions (they are principally the reactions referenced to Sections 17.5 and beyond). As you use this summary, you will find it helpful to also review Section 17.4, which presents the general nucleophilic addition-elimination mechanism for acyl substitution. It is instructive to relate aspects of the specific acyl substitution reactions below to this general mechanism. In some cases proton transfer steps are also involved, such as to make a leaving group more suitable by prior protonation or to transfer a proton to a stronger base at some point in a reaction, but in all acyl substitution the essential nucleophilic addition-elimination steps are identifiable. 

Carbonylation offers yet another opportunity for oxidation. In CO the formal oxidation state (FOS) of the carbon atom is +2. In cases where the carbonylation products are carboxylic acids and their derivatives, the FOS of the carbonyl carbon atom is -i-3. If they are carbonates and related derivatives, it is +4. These changes in the FOS, that is, +2 -1-3 and +4, do not necessarily mean that carbonylation reactions in question... 

In the previous section, synthesis of pyrimidine derivatives bearing fluorinated alkyl substituent at C-2 atom was discussed. Derivatives of fluorinated carboxylic acids and related compounds were used as the fluorine sources. The most important method for the preparation of other chain-fluorinated pyrimidines is the principal synthesis from fluoroalkyl-substituted three-carbon bis-electrophiles (e.g. p-dicarbonyl compounds). A huge number of fluorinated bis-electrophiles were introduced in the principal synthesis of pyrimidines bearing fluoroalkyl substituent at C-4 atom of the heterocyclic ring (Fig. 24), including fluorine-containing ... 

Salts and esters of carboxylic acids and related compounds are named by placing the name of the metal or the esterifying group in front of the name of the acid anion, separated by a space. Joint occurrence of both functions is indicated accordingly. Acid salts and esters are named analogously. Complex cases can also be named more descriptively ... salt or. .. ester of. .. acid. (Similar provisions are valid for other acid derivatives such as amides and nitriles.)... 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

The reaction is less selective than the related benzoylation reaction (/pMe = 30.2, cf. 626), thereby indicating a greater charge on the electrophile this is in complete agreement with the greater ease of nuclophilic substitution of sulphonic acids and derivatives compared to carboxylic acids and derivatives and may be rationalized from a consideration of resonance structures. The effect of substituents on the reactivity of the sulphonyl chloride follows from the effect of stabilizing the aryl-sulphonium ion formed in the ionisation step (81) or from the effect on the preequilibrium step (79). 

In the course of this study, the authors determined /Lvalues for dibenzyl, methyl phenyl, methyl p-nitrophenyl, di-p-tolyl, di-isopropyl and tetramethylene sulphoxides and for diethyl, dipropyl and dibutyl sulphites. The /Lscales are applied to the various reactions or the spectral measurements. The /Lscales have been divided into either family-dependent (FD) types, which means two or more compounds can share the same /Lscale, family-independent (FI) types. Consequently, a variety of /Lscales are now available for various families of the bases, including 29 aldehydes and ketones, 17 carboxylic amides and ureas, 14 carboxylic acids esters, 4 acyl halides, 5 nitriles, 10 ethers, 16 phosphine oxides, 12 sulphinyl compounds, 15 pyridines and pyrimidines, 16 sp3 hybridized amines and 10 alcohols. The enthalpies of formation of the hydrogen bond of 4-fluorophenol with both sulphoxides and phosphine oxides and related derivatives fit the empirical equation 18, where the standard deviation is y = 0.983. Several averaged scales are shown in Table 1588. 

Hydroxycarbonylation and alkoxycarbonylation of alkenes catalyzed by metal catalyst have been studied for the synthesis of acids, esters, and related derivatives. Palladium systems in particular have been popular and their use in hydroxycarbonylation and alkoxycarbonylation reactions has been reviewed.625,626 The catalysts were mainly designed for the carbonylation of alkenes in the presence of alcohols in order to prepare carboxylic esters, but they also work well for synthesizing carboxylic acids or anhydrides.137 627 They have also been used as catalysts in many other carbonyl-based processes that are of interest to industry. The hydroxycarbonylation of butadiene, the dicarboxylation of alkenes, the carbonylation of alkenes, the carbonylation of benzyl- and aryl-halide compounds, and oxidative carbonylations have been reviewed.6 8 The Pd-catalyzed hydroxycarbonylation of alkenes has attracted considerable interest in recent years as a way of obtaining carboxylic acids. In general, in acidic media, palladium salts in the presence of mono- or bidentate phosphines afford a mixture of linear and branched acids (see Scheme 9). 

A recent report indicates that thiophenes (not benzothiophenes) may be formed from alkyl phenyl ketones by treatment with a slight excess of thionyl chloride in the cold.58 Propiophenone, for example, yields 3,4-dibenzoyl-thiophene (47). Adipic acid and related carboxylic acids yield thiophene derivatives upon treatment with thionyl chloride in the presence of pyridine.59... 

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