Carboxylic acid derivatives esters

Calixarenes, which are macrocyclic compounds, are one of the best building blocks to design molecular hosts in supramolecular chemistry [158]. Synthesis of calix[4]arenes, which have been adamantylated, has been reported [105, 109]. In calix[4]arenes, adamantane or its ester/carboxylic acid derivatives were introduced as substituents (Fig. 29). The purpose of this synthesis was to learn how to employ the flexible chemistry of adamantane in order to construct different kinds of molecular hosts. The X-ray structure analysis of p-(l-adamantyl)thiacalix[4]arene [109] demonstrated that it contained four CHCI3 molecules, one of which was located inside the host molecule cavity, and the host molecule assumed the cone-like conformational shape (Fig. 30). 

Hirose S, Hatakeyama T, Hatakeyama H (2005) Glass transition and thermal decomposition of epoxy resins from the carboxylic add system consisting of ester-carboxylic acid derivatives of alcoholysis lignin and ethylene glycol with various eicarboxyUc adds. Thermochim Acta 431 76-80... 

Activated Adds Chern. Soc. Rev. 1983, 12, 129 Angew. Chern. fnt. Ed. Engl. 1978, 17, 569. RC02F4 "activated acid" carboxylic acid derivative (ester, amide, etc.)... 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

Conversion of Esters to Other Carboxylic Acid Derivatives... 

The carbonyl group of an amide is stabilized to a greater extent than that of an acyl chlo ride acid anhydride or ester amides are formed rapidly and m high yield from each of these carboxylic acid derivatives... 

This chapter concerns the preparation and reactions of acyl chlorides acid anhydrides thioesters esters amides and nitriles These com pounds are generally classified as carboxylic acid derivatives and their nomenclature is based on that of carboxylic acids... 

Carboxylic acid derivative (Section 20 1) Compound that yields a carboxylic acid on hydrolysis Carboxylic acid de nvatives include acyl chlondes acid anhydndes esters and amides... 

C, which decomposes when heated above the melting point. Its solubility at 25°C in g/100 g solvent is water. 111 methanol, 5 ethanol, 1.4 acetone, 0.04 and carbon tetrachloride, 0.004. Because its carbon—fluorine bond is unreactive under most conditions, this salt can be converted by standard procedures to typical carboxylic acid derivatives such as fluoroacetyl esters (11,12), fluoroacetyl chloride [359-06-8] (13), fluoroacetamide (14), or fluoroacetonitrile [503-20-8] (14). 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

The cinnamyl ester can be prepared from an activated carboxylic acid derivative and cinnamyl alcohol it is cleaved under nearly neutral conditions [Hg(OAc)2, MeOH, 23°, 2-4 h KSCN, H2O, 23°, 12-16 h, 90% yield]. 

Solid esters are easily crystallisable materials. It is important to note that esters of alcohols must be recrystallised either from non-hydroxylic solvents (e.g. toluene) or from the alcohol from which the ester is derived. Thus methyl esters should be crystallised from methanol or methanol/toluene, but not from ethanol, n-butanol or other alcohols, in order to avoid alcohol exchange and contamination of the ester with a second ester. Useful solvents for crystallisation are the corresponding alcohols or aqueous alcohols, toluene, toluene/petroleum ether, and chloroform (ethanol-free)/toluene. Esters of carboxylic acid derived from phenols... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

Electrochemical fluonnation ot N,N dialkylammo-substituted carboxylic acids as their methyl esters produces the analogous perfluonnated tertiary amine carboxylic acid derivatives in 18-30% yields as well as cyclic amine ethers [JOO]... 

Correlations with o in carboxylic acid derivative reactions have been most successful for variations in the acyl portion, R in RCOX. Variation in the alkyl portion of esters, R in RCOOR, has not led to many good correlations, although use of relative rates of alkaline and acidic reactions, as in the defining relation, can generate linear correlations. The failure to achieve satisfactory correlations with cr for such substrates may be a consequence of the different steric effects of substituents in the acyl and alkyl locations. It has been shown that solvolysis rates of some acetates are related to the pA", of the leaving group, that is, of the parent alcohol. The pK of alcohols has been correlated with but this relationship... 

Most acid-catalyzed hydrolyses of carboxylic acid derivatives proceed by the A2 mechanism, as shown for ester hydrolysis ... 

The cinnamyl ester can be prepared from an activated carboxylic acid derivative and cinnamyl alcohol or by transesterification with cinnamyl alcohol in the presence of the H-Beta Zeolite (toluene, reflux, 8 h, 59-96% yield). It is cleaved under nearly neutral conditions [Hg(OAc)2, MeOH, 23°, 2-A h KSCN, H2O, 23°, 12-16 h, 90% yield]or by treatment with Sulfated-Sn02, toluene, anisole, reflux. The latter conditions also cleave crotyl and prenyl esters. 

Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4//-pyrido-[l,2-u]pyrimidin-4-ones 289 by heating in 85% phosphoric acid, or in PPA yielded 7,12-dihydropyrimido[l, 2 l,2]pyrido[3,4-Z)]indol-4(6//)-ones 290 (96JHC799, 99MI12, 00MI22). From the 3-ester and 3-carboxylic acid derivatives 289 (R = COOEt, COOH) and decarboxylated products 290 (R = H) were obtained. 

Reaction of 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l, 2,3- e]-1,4-ben-zothiazine-6-carboxylic acid and its ethyl ester with B(OH)3 in AC2O in the presence of ZnCl2 afforded 6-[(diacetoxyboryl)oxycarbonyl] derivative 323 (R = OAc)], which was reacted with primary and cyclic amines to give 10-amino-9-fluoro-7-carboxylic acid derivatives 324 (97MI41, 98MI30). 6-[(Difluoroboryl)oxycarbonyl derivative 323 (R = F) was obtained from ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate with BF3-THF complex. Reaction of 323 (R = F) and 1-methylpiperazine in DMF at 50-60 °C and subsequent acidic hydrolysis afforded 7 (97MI1). 

A third method of aldehyde synthesis is one that we ll mention here just briefly and then return to in Section 21.6. Certain carboxylic acid derivatives can be partially reduced to yield aldehydes. The partial reduction of an ester by dhsobutylaluminum hydride (DIBAH), for instance, is an important laboratory-scale method of aldehyde synthesis, and mechanistically related processes also occur in biological pathways. The reaction is normally carried out at —78 °C (dry-ice temperature) in toluene solution. 

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. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Esters undergo the same kinds of reactions that we ve seen for other carboxylic acid derivatives, but they are less reactive toward nucleophiles than either acid chlorides or anhydrides. All their reactions are equally applicable to both acyclic and cyclic esters, called lactones. 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

Carboxylic acids can be transformed into a variety of carboxylic acid derivatives in which the carboxyl -OH group has been replaced by another substituent. Acid halides, acid anhydrides, esters, and amides arc the most common such derivatives in the laboratory thioesters and acyl phosphates are common in biological molecules. 

The most common reactions of carboxylic acid derivatives are substitution by water (hydrolysis) to yield an acid, by an alcohol (alcoholysis) to yield an ester, by an amine (aminolysis) to yield an amide, by hydride ion to yield an alcohol (reduction), and by an organometallic reagent to yield an alcohol (Grignard reaction). 

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