Direct catalysis decarboxylation reactions

Jencks and coworkers9 noted that a likely route for catalysis of carboxylation reactions (replacement of a proton by a carboxyl group) is the generation of low entropy carbon dioxide by a reaction of ATP and bicarbonate adjacent to Nl of biotin. This way of promoting carboxylation produces a situation which is precisely what is created at the stage of the initial formation of products in decarboxylation reactions. Since there is no directional momentum, the proximity of low entropy carbon dioxide and a nucleophile similarly will slow the reaction in the direction of decarboxylation. The same authors suggest that for decarboxylation reactions, nucleophilic addition to carbon dioxide in an enzyme s active site would prevent re-addition and promote the forward reaction if the addition product is itself sufficiently unstable. 

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. 

Oxidathe deaerboxylatUm. Heating fluorene-9-carboxyl ic acid (1) with 2.0 molar eq. of basic copper carbonate affords fluorenone (2, 56% yield). This reaction is the first report of a direct oxidative decarboxylation with copper salt catalysis. 

First steps to elucidate the reaction mechanism of PDC were achieved by the investigation of model reactions using ThDP or thiamine [36,37], Besides the identification of C2-ThDP as the catalytic center of the cofactor [36], the mechanism of the ThDP-catalyzed decarboxylation of a-keto acids as well as the formation of acyloins was explained by the formation of a common reaction intermediate, active acetaldehyde . This active species was first identified as HEThDP 7 (Scheme 3) [38,39]. Later studies revealed the a-carbanion/enamine 6 as the most likely candidate for the active acetaldehyde [40 47] (for a comprehensive review see [48]). The relevance of different functional groups in the ThDP-molecule for the enzymatic catalysis was elucidated by site-directed substitutions of the cofactor ThDP by chemical means (for a review see... 

O/t/20-arylation of benzoic acids is often preferable to ortho-arylation of benzamides if conversion of the amide moiety to other functional groups is desired. However, only a few reports have dealt with the orf/io-functionalization of free benzoic acids due to challenges that involve such transformations. The reactions can be complicated by decarboxylation of the product and the starting material. Despite those difficulties, several methods for direct o/t/io-arylation of benzoic acids have been developed. Yu has shown that arylboronates are effective in arylation of benzoic acids under palladium catalysis [59], The reactions require the presence of palladium acetate catalyst, silver carbonate oxidant, and benzoquinone. Even more interestingly, the procedure is applicable to the arylation of unactivated sp3 C-H bonds in tertiary carboxylic acids such as pivalic acid (Scheme 13) if aryl iodide coupling partner is used. Aryl trifluoroborates can also be used [60],... 

In analyzing the origin of enzyme catalysis, Warshel and others have advocated the importance of comparing the enzymatic reaction with a reference reaction in water [32]. In addition, it is also necessary to study the reference reaction in the gas phase in order to understand the intrinsic reactivity and the effect of solvation. Thus, to understand enzyme catalysis fully, we must compare results for the same reaction in the gas phase (intrinsic reactivity), in aqueous solution (solvation effects), and in the enzyme (catalysis). This is not possible when there is no model reaction for the uncatalyzed process in the gas phase and in water, or if the uncatalyzed reaction is a bimolecular process as opposed to a unimolecular reaction in the enzyme active site. None of these problems apply to the ODCase reaction. Furthermore, OMP decarboxylation is a unimolecular process, both in water and the enzyme, providing an excellent opportunity to compare directly the computed free energies of activation [1] this is the approach that we have undertaken [16]. Warshel et al. used an ammonium ion-orotate ion pair fixed at distances of 2.8 or 3.5 A as the reference reaction in water to mimic an active site lysine residue [32]. 

C-H alkenylation and decarboxylation (Scheme 4.48) [53], as in the reaction of benzoic acids described above (Schemes 4.28 and 4.29). Since the palladium-catalyzed Fujiwara-Moritani type direct alkenylation of indoles usually takes place at the C3-position, it enables alkenylation at a position complementary to that of the Fujiwara-Moritani reaction, being of unique synthetic utility. On the other hand, the reaction of thiophene-2-carboxylic acid leads to the formation of a mixture of C2- and C3-alkenylated products. Decarboxylation may take place too early to complete directed C-H alkenylation at the C3-position. In contrast, the exclusive C3-alkenylation on a thiophene ring is possible under rhodium catalysis (Scheme 4.49) [34b]. 

The main focus of this chapter is homogeneous catalysis which involves the cleavage of C-C=0 and C-CN bonds. Catalytic reactions are categorized in the following order (i) type of bond cleaved (ii) mechanism (oxidative addition, others, and unclear) and (iii) strategy (directed, non-directed, and others). Related stoichiometric reactions are also given when necessary. For catalytic reactions via decarboxylation of a-keto carboxylic acids, refer to Chapter 4. 

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