Carboxylic acids, conjugated decarboxylation

We have presented evidence that pyrrole-2-carboxylic acid decarboxylates in acid via the addition of water to the carboxyl group, rather than by direct formation of C02.73 This leads to the formation of the conjugate acid of carbonic acid, C(OH)3+, which rapidly dissociates into protonated water and carbon dioxide (Scheme 9). The pKA for protonation of the a-carbon acid of pyrrole is —3.8.74 Although this mechanism of decarboxylation is more complex than the typical dissociative mechanism generating carbon dioxide, the weak carbanion formed will be a poor nucleophile and will not be subject to internal return. However, this leads to a point of interest, in that an enzyme catalyzes the decarboxylation and carboxylation of pyrrole-2-carboxylic acid and pyrrole respectively.75 In the decarboxylation reaction, unlike the case of 2-ketoacids, the enzyme cannot access the potential catalysis available from preventing the internal return from a highly basic carbanion, which could be the reason that the rates of decarboxylation are more comparable to those in solution. Therefore, the enzyme cannot achieve further acceleration of decarboxylation. In the carboxylation of pyrrole, the absence of a reactive carbanion will also make the reaction more difficult however, in this case it occurs more readily than with other aromatic acid decarboxylases. 

For applied purposes, the book by Mitskevich and Erofeev [31] is of interest because it discusses conjugated reactions on the example of decarboxylation processes accompanying the liquid-phase oxidation of carboxylic acids. 

Mitskevich, N.I. and Erofeev, B.V., Conjugated Oxidation and Decarboxylation of Carboxylic Acids, Nauka i Tekhnika, Minsk, 1970, 188 pp. (in Russian). 

As already pointed out, cysteine may be metabolized to pyruvate, or it can be oxidized to cystine. It can also be converted to taurine, NH3+-CH2-CH2-S03. Taurine is obtained by oxidizing the -SH group of cysteine and losing the carboxyl group of decarboxylation. Taurine is quite abundant in most tissues and is said to be the most abundant "amino acid" of the human organism. One of its functions is to conjugate primary bile acids (Chapter 19). 

In some examples, the stereochemistry of radical reactions was controlled by chiral carbohydrate auxiliaries. As a radical counterpart to the ionic conjugate additions discussed above, Garner et al. [169] prepared carbohydrate linked radicals that were reacted with a,P-unsaturated esters. The radical precursor, the carboxylic acid 256, generated by the addition of ( Sj-methyl lactate to tri-O-benzyl-D-glucal and subsequent ester hydrolysis, was decarboxylated by Barton s procedure (Scheme 10.84) [170]. Trapping of the chiral radical 258 with methyl acrylate furnished the saturated ester 259 in 61% yield and with high diastereoselectivity (11 1). The auxiliary caused a preferential addition to the si-facQ of radical 258, probably due to entropic effects. The ester 259 was transformed in acceptable yield to the y-butyrolactone 261 by reductive removal of the thiopyridyl group followed by acid hydrolysis. 

Analogous carboxylic acids containing conjugated double bonds can also often be decarboxylated, the conjugation being no longer present in the product ... 

Alternative preparations of 2-allyl-3-methylcyclohexanone include a) lithium-ammonia reduction of 2-allyl-3 methylcyclohex-2-enone (see Note 13), which can be prepared by alkylation of 3-methjdcyclohex-2-enone or by alkjdation of 4-carboethoxy-3-methylcyclohex-2-enone [Hagemann s ester 2-Cyclohexene-l-carboxylic acid, 2-inethyl-4-oxo-, ethyl ester], followed bj hydrolysis and decarboxylation and b) conjugate addition of lithium dimethylcupratc [Cuprate (1-), dimethyl-, lithium] to 2-cyolohexen-l-one followed by trapping of the enolate with allyl iodide or allyl bromidein an appropriate solvent. 

Hydrogenolysis of benzyl ester 202 furnished N-1 unsubstituted carboxylic acid 201 (R = H, = Me, X = O), which on decarboxylation yielded C-5 unsubstituted derivatives (76M587). While N-1 unsubstituted 22 (R = H, X = O) are inert toward acid or base hydrolysis, N-1 methyl 22 (R = Me, X = O) was saponified using 5% alcoholic KOH to carboxylic acid 201 (R = Me) (Scheme 76). The unreactivity of the ester may be attributed to strong conjugation with the adjacent vinylic alkene, supported by the fact that the hexahydropyrimidine carboxylic ester is readily hydrolyzed (33JA3781). 

The mechanisms of a few representative reactions are illustrated in the hydrogenation of alkene (Scheme 1), the decarboxylation of conjugated carboxylic acid (Scheme 2), and the dehydrogenation of diols (Scheme 3). 

Conjugate addition (1,4 addition) of pyridine and ionization of a carboxylic acid are followed by decarboxylation and concomitant elimination of pyridine to yield the a,p-unsaturated carboxylic add as shown here. 

The substituted vinyl-)3-lactone undergoes ring-opening isomerization to form 2,4-dienecarboxylic acid in aprotic solvents in the presence of catalytic amount of Pd(OAc)2. Addition of trimethyl phosphite led to almost quantitative isomerization into the unsaturated acid. However, decarboxylation-elimination to form a conjugate diene proceeded in DMF or DMSO.t The quantitative evolution of CO2 in good coordinating aprotic solvents is explained by a poor solvation of the carboxylate anion through the carboxylate (Scheme 12). 

Salts and esters of carboxylic acids are called carboxylates. When a carboxyl group is deprotonated, its conjugate base, a carboxylate anion is formed. Carboxylate ions are resonance stabilized and this increased stability makes carboxylic acids more acidic than alcohols. Carboxylic acids can be seen as reduced or alkylated forms of the Lewis acid carbon dioxide under some circumstances they can be decarboxylated to yield carbon dioxide. 

The in situ generation of carbon nucleophiles via extrusion of CO2 from benzoates cannot only be combined with cross-coupling processes but also with 1,2- and 1,4-addition reactions. An example is the rhodium-catalyzed decarboxylative conjugate addition of activated benzoic acids to acrylic esters or amides developed by Zhao et al. (Scheme 19, right side) [65]. A nice application is the decarboxylative addition of aromatic carboxylic acids to nitriles in the presence of... 

Neither reaction occurs for the conjugate base of these acids because a proton is required for transfer between oxygen atoms. If the conjugate base is carefully neutralized, the carboxylic acid can be isolated at room temperature without decarboxylation. 

Decarboxylation of copolymers of propynoic acid and phenylacetylene of varying composition was found to manifest an increase in reactivity of the carboxylic groups with increasing concentration of conjugated double bonds in the chain. 

The chemical reactivity of resin acids is determined hy the presence of hoth the double- bond system and the COOH group [5], The carboxylic group is mainly involved in esterification, salt formation, decarboxylation, nitrile and anhydrides formation, etc. These reactions are obviously relevant to both abietic- and pimaric-type acids (Rgs 4.1 and 4.3, respectively). The olefinic system can be involved in oxidation, reduction, hydrogenation and dehydrogenation reactions. Given the conjugated character of this system in the abietic-type acids, and the enhanced reactivity associated with it, much more attention has been devoted to these stractures. In terms of industrial applications, salt formation, esterification, and Diels-Alder additions are the most relevant reactions of resin acids. 

Another conjugate addition strategy used the sodium enolate of 4.62 in a reaction with ketene 4.63 to give 4.64. In this particular example, both the amino and the carboxyl moieties of the final amino acid were present in the starting material (4.62). Aqueous acid hydrolysis of the ester groups and the amide was accompanied by decarboxylation to give 2-amino-3-methylenebutanedioic acid, 4.55.33... 

The labile bond is always the one perpendicular to the pyridine ring and combined ionic, polar, and hydrophobic interactions on the enzyme determine which conformer predominates. This is easily seen for example in the Newman projection of enzymatic decarboxylation. The conformation required for decarboxylation places the carboxyl group substantially out of the plane of the conjugated system. Consequently, the specificity of the reaction is manifested principally at this stage. For instance, enzymatic decarboxylation of amino acids occurs with retention of configuration and thus allows the preparation of optically pure a-deuterated amines if the reaction is carried out in heavy water (304). 

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