Carboxylic acids, from acyl alcohols

The reaction of trivalent carbocations with carbon monoxide giving acyl cations is the key step in the well-known and industrially used Koch-Haaf reaction of preparing branched carboxylic acids from al-kenes or alcohols. For example, in this way, isobutylene or tert-hutyi alcohol is converted into pivalic acid. In contrast, based on the superacidic activation of electrophiles leading the superelectrophiles (see Chapter 12), we found it possible to formylate isoalkanes to aldehydes, which subsequently rearrange to their corresponding branched ketones. 

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

Lipase-catalyzed acylation of one isomer of iV-hydroxymethyl /3-lactam 121 by vinyl butyrate in acetone yielded the ester 122, which afforded 123 after acidic hydrolysis and ion-exchange chromatography (Scheme 7). The unesterified alcohol 124 gave the /3-amino acid 125. Similar reactions yielded 2-aminocyclohex-3-en-l-carboxylic acid and 2-aminocyclohex-4-ene-l-carboxylic acid from l-azabicyclo[4.2.0]oct-3-en-8-one and l-azabicyclo[4.2.0]oct-... 

It is rather difficult to convert carboxylic acids to decarboxylative alcohols. However, treatment of O-acyl esters (2) in the presence of Sb(SPh)3 and molecular oxygen, followed by hydrolysis, generates the corresponding decarboxylative alcohols. Eq. 8.11 shows the preparation of a sex pheromone of the citrus mealybug from (+ )-ds-pinonic acid [30-32]. When 1802 instead of 1602, is used in this reaction, 180-alcohols can be obtained. 

Esters can also be synthesized by a nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol. Fischer and Speier discovered in 1895 that esters result simply from heating a carboxylic acid in alcohol solution containing a small amount of strong acid catalyst. Yields are good in this Fischer esterification reaction, but the need to use excess alcohol as solvent limits the method to the synthesis of methyl, ethyl, and propyl esters. 

Section 15.3 described the reduction of carboxylic acids to primary alcohols with lithium aluminum hydride. Esters are more easily reduced than carboxylic acids. Two alcohols are formed from each ester molecule, with cleavage of the acyl group of the ester giving a primary alcohol. 

The reactions of lipids represent many reactions that we have studied in previous chapters, especially reactions of carboxylic acids, alkenes, and alcohols. Ester hydrolysis (e.g., saponification) liberates fatty acids and glycerol from triacylg-lycerols. The carboxylic acid group of a fatty acid can be reduced, converted to an activated acyl derivative such as an acyl chloride, or converted to an ester or amide. Alkene functional groups... 

The first step of phenylpropanoid biosynthesis is conversion of phenylalanine into cinnamic acid by cleavage of ammonium group by the enzyme phenylalanine ammonia-lyase (PAL). Reduction of carboxylic acid from the cinnamic acid leads to cinnamaldehyde, which is then acylated with acetate from acetyl-CoA to form coniferyl alcohol [14]. Reductive cleavage of coniferyl alcohol by eugenol synthase yields eugenol [15]. 

The conversion of carboxylic acids into acyl halides employs the same reagents used in the synthesis of haloalkanes from alcohols (Section 9-4) SOCI2 and PBrs. The problem to be solved in both cases is identical—changing a poor leaving group (OH) into a good one. 

The reaction occurs by a nucleophilic acyl substitution pathway in which the carboxylic acid is first converted into a chlorosulfite intermediate, thereby replacing the -OH of the acid with a much better leaving group. The chloro-sulfitc then reacts with a nucleophilic chloride ion. You might recall from Section 17.6 Hint an analogous chlorosulfite is involved in reaction of an alcohol with SOCb to yield an alkyl chloride. 

The main synthetic application of the Wolff rearrangement is for the one-carbon homologation of carboxylic acids.242 In this procedure, a diazomethyl ketone is synthesized from an acyl chloride. The rearrangement is then carried out in a nucleophilic solvent that traps the ketene to form a carboxylic acid (in water) or an ester (in alcohols). Silver oxide is often used as a catalyst, since it seems to promote the rearrangement over carbene formation.243... 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

Since the imidazolide method proceeds almost quantitatively, it has been used for the synthesis of isotopically labeled esters (see also Section 3.2), and it is always useful for the esterification of sensitive carboxylic acids, alcohols, and phenols under mild conditions. This advantage has been utilized in biochemistry for the study of transacylating enzymes. A number of enzymatic transacylations (e.g., those catalyzed by oc-chymo-trypsin) have been shown to proceed in two steps an acyl group is first transferred from the substrate to the enzyme to form an acyl enzyme, which is then deacylated in a second step. In this context it has been shown[21] that oc-chymotrypsin is rapidly and quantitatively acylated by Af-fraw.s-cinnamoylimidazole to give /ra/w-cinnamoyl-a-chymotrypsin, which can be isolated in preparative quantities and retains its enzymatic activity (see also Chapter 6). 

For carboxyl terminal determination of peptides by means of CDI the terminal carboxylic acid group of the peptide is selectively reduced with sodium dihydrobis(2-methoxy-ethoxy)aluminate to an alcohol. Subsequent conversion of the amino alcohol moiety with CDI yields an 7V-acyl-2-oxazolidone derivative, from which the oxazolidone unit can be easily removed and characterized.[56]... 

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