Carboxylic acids, from acyl

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. 

FIGURE 20.1 Structure, reactivity, and carbonyl-group stabilization in carboxylic acid derivatives. Acyl chlorides are the most reactive, amides the least reactive. Acyl chlorides have the least stabilized carbonyl group, amides the most. Conversion of one class of compounds to another is feasible only in the direction that leads to a more stabilized carbonyl group that is, from more reactive to less reactive. 

The reaction between carbonium ions and carbon monoxide affording oxocarbonium ions (acyl cations) is a key step in the well-known Koch reaction for making carboxylic acids from alkenes, carbon monoxide and water ... 

Aldehydes have been prepared from carboxylic acids or acyl halides by first converting them to certain types of amides that are easily reducible. The following are some examples ... 

A potential liability associated with such reductive hydroacylations resides in the fact that only one acyl residue of the symmetric anhydride is incorporated into the coupling product. For more precious carboxylic acids, selective acyl transfer from mixed anhydrides is possible. Mixed anhydrides derived from pivalic acid are especially convenient, as they may be isolated chromato-graphically in most cases. In practice, mixed anhydrides of this type enable completely branch-selective hydroacylation with selective delivery of the aromatic and a,()-unsalurated acyl donors (Scheme 19). 

Examples of the synthesis of other hydrazides from carboxylic acids and acyl- or alkylhydrazines are provided below [75] [171]... 

Like in Chapt. 7, we begin the discussion with acetates, since acetic acid is the simplest nontoxic acyl group, formic acid being less innocuous. An informative study was carried out to compare the kinetics of hydrolysis of two types of corticosteroid esters, namely methyl steroid-21-oates (which are active per se) and acetyl steroid-21-ols (which are prodrugs), as exemplified by methyl prednisolonate (8.69) and prednisolone-21-acetate (8.70), respectively [89]. In the presence of rat liver microsomes, the rate of hydrolytic inactivation of methyl steroid-21-oates was much slower than the rate of hydrolytic activation of acetyl steroid-21-ols. Thus, while the Km values were ca. 0.1 -0.3 mM for all substrates, the acetic acid ester prodrugs and the methyl ester drugs had Vmax values of ca. 20 and 0.15 nmol min-1 mg-1, respectively. It can be postulated that the observed rates of hydrolysis were determined by the acyl moiety, in other words by the liberation of the carboxylic acid from the acyl-enzyme intermediate (see Chapt. 3). 

The name anhydride means without water, so that makes it pretty clear that the general idea behind the formation of an acid anhydride is to remove water from a carboxylic acid. Both acyl chlorides and acid anhydrides are very effective at removing water. In some cases, heat can be used to remove water. 

Acylium ions can be formed in superacid solutions from carboxylic acids and acyl halides (8). They are among the best characterized carbenium ions, and single-crystal X-ray structures of a number of them have been determined as BFf, SbFg, or TaClfi salts (135-139). Solid-state NMR characterization of these species on AlBr3 and other solid superacids was described earlier in this review. 

Further support for the intermolecular route is provided by the isolation of the substituted trans-cinnamic acid, the normal Perkin product. This arises through elimination of carboxylic acid from the fully acylated species (393) rather than cyclization. For example, a considerable amount of 2-acetoxy-3-methoxycinnamic acid is formed from 3-methoxysalicylaldehyde, perhaps as a result of steric interference with cyclization so allowing the intermolecular process to predominate (39JPR(152)23). It should be noted that trans- 2-hydroxycinnamic acids do not cyclize under normal Perkin conditions, though the cis isomer does so quite readily. Isomerization of the trans acid has been effected by treatment with a trace of iodine in acetic anhydride or by UV irradiation. 

A triketone is also an intermediate in a synthesis of 6-methyI-4-oxopyran-2-carboxylic acid from pentane-2,3-dione in which one carbonyl group is initially protected as the ketal (67JOC4105). Acylation by ethyl oxalate is accomplished under basic conditions, and ring closure and hydrolysis of the ketal are effected with acid. 

From reduction of carboxylic acids and acyl derivatives Sodium borohydride, 278 Sodium cyanoborohydride-Tin(II) chloride, 280... 

From carboxylic acids or acyl derivatives Aluminum chloride, 15 1-Benzotriazolyl diethyl phosphate, 28 Bis(dichloroaluminum)phenylimide,... 

As reported in the literature, the acylation of aromatic hydrocarbons can be carried out by using zeolites as catalysts and carboxylic acids or acyl chlorides as acylating agents. Thus toluene can be acylated by carboxylic acids in the liquid phase in the presence of cation exchanged Y-zeolites (ref. 1). The acylation of phenol or phenol derivatives is also reported. The acylation of anisole by carboxylic acids and acyl chlorides was obtained in the presence of various zeolites in the liquid phase (ref. 2). The acylation of phenol by acetic acid was also carried out with silicalite (ref. 3) or HZSM5 (ref. 4). The para isomer has been generally favoured except in the latter case in which ortho-hydroxyacetophenone was obtained preferentially. One possible explanation for the high ortho-selectivity in the case of the acylation of phenol by acetic acid is that phenylacetate could be an intermediate from which ortho-hydroxyacetophenone would be formed intramolecularly. 

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... 

The Koch-Haaf reaction397 for the preparation of carboxylic acids from alkenes uses formic acid or carbon monoxide in strongly acidic solutions. The reaction between carbocations and carbon monoxide affording oxo-carbenium ions (acyl cations) is a... 

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-... 

The ammonolysis of acyl chlorides is commonly employed whenever the preparation of an amide is desired for the identification of a carboxylic acid. The acyl chloride is prepared and treated with aqueous ammonia, or, if the amide is very soluble in water, with ammonia in benzene. In the latter case the ammonium chloride is filtered off, and the amide obtained by evaporation of the benzene with powdered ammonium carbonate. The preparation of amides from carboxylic acids is based upon the formation of an equilibrium mixture when the ammonium salts of the acid are heated ... 

In a direct route from carboxylic acids to acyl azides diphenyl phosphorazidate is used probably the reaction passes through a cyclic transition state (Scheme 41). With aromatic and heteroaromatic educts, yields as high as 75% may be obtained. If aliphatic acids are treated under the same conditions, the corresponding azides are, however, immediately transformed into urethanes via isocyanates. Aroyl azides can also be obtained in excellent yields by reaction of carboxylic acids with NaNa and phenyl di-chlorophosphate in the presence of tetrabutylammonium bromide or pyridine (Scheme 41). ... 

Mixed carboxylic-carbonic anhydrides, prepared from carboxylic acids and alkyl chloioformates in the presence of base, are easily converted to acyl azides by the action of sodium azide. Since the reaction sequence from carboxylic acids to acyl azides proceeds under mild conditions, it has a broad applica-... 

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