Nucleophilic with carboxylic acid nucleophiles

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

In the previous review (91YGK205, 99H1157), we reported that l-hydroxy-4-nitroindole forms active ester derivatives by reaction with carboxylic acids, which can be applied to acylation of various nucleophiles. To expand the scope of the reaction and obtain novel fungicidal compounds, an attempt has been made to prepare derivatives of wasabi phytoalexin 109 (98P1959). 

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

Examples of polyfunctional carboxylic acids esterified by this method are shown in Table I. Yields are uniformly high, with the exception of those cases (maleic and fumaric acids) where some of the product appears to be lost during work-up as a result of water solubility. Even with carboxylic acids containing a second functional group (e.g., amide, nitrile) which can readily react with the oxonium salt, the more nucleophilic carboxylate anion is preferentially alkylated. The examples described in detail above illustrate the esterification of an acid containing a labile acetoxy group, which would not survive other procedures such as the traditional Fischer esterification. 

Phenolic compounds are weaker nucleophiles and better leaving groups than aliphatic alcohols. They do not yield polyesters when reacted with carboxylic acids or alkyl carboxy lates. The synthesis of polyesters from diphenols is, therefore, generally carried out through the high-temperature carboxylic acid-aryl acetate or phenyl ester-phenol interchange reactions with efficient removal of reaction by-product (Schemes 2.10 and 2.11, respectively). 

Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exemplified by the iodolactonization reaction71 Reaction of iodine with carboxylic acids having carbon-carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones. The reaction shows a preference for formation of five- over six-membered72 rings and is a stereospecific anti addition when carried out under basic conditions. 

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... 

N-substituted carbodiimides can react with carboxylic acids to form highly reactive, o-acylisourea derivatives that are extremely short-lived (Reaction 11). This active species then can react with a nucleophile such as a primary amine to form an amide bond (Reaction 12)... 

Chemical groups that specifically react with carboxylic acids are limited in variety. In aqueous solutions, the carboxylate functionality displays rather low nucleophilicity. For this reason, it is unreactive with the great majority of bioconjugate reagents which couple through a nucleophilic addition process. 

Figure 3.1 EDC reacts with carboxylic acids to create an active-ester intermediate. In the presence of an amine nucleophile, an amide bond is formed with release of an isourea by-product.

Biotin-hydrazide also may be used to couple with carboxylate-containing molecules. Hydrazidcs can be coupled with carboxylic acid groups by using the carbodiimide reaction (Chapter 3, Section 1.1). The carbodiimide activates a carboxylate to an o-acylisourea intermediate. Biotin-hydrazide can react with this intermediate via nucleophilic addition to form a stable covalent bond. 

Thiols undergo the same types of nucleophilic reaction with carboxylic acid derivatives as do alcohols. However, reactivity tends to be increased for two reasons. First, sulfur, because of its larger size, is a better nucleophile than oxygen (see... 

The reaction of carbon nucleophiles derived from organometallics with carboxylic acid derivatives follows closely the reactions we have already encountered in Sections 6.3.2 and 7.6.2. Organometallics... 

Acy 1-4-amino-1,5-dihydro-2-pyrrolones (6) (type Z in Scheme 1) possess the features of cyclic enaminediones. The push-pull-7r system decreases the nucleophilicity of the amino group. Therefore N-acylation with carboxylic acid chlorides requires relatively drastic conditions (dioxane, 100°C, K2C03). In particular, the reaction of the highly reactive DMF-acetal 8 to formamidine 9 succeeds only while refluxing in benzene (87TH1). (See Fig. 3.)... 

A nucleophile is an electron rich species that reacts with an electrophile. The term electrophile literally means electron-loving , and is an electron-deficient species that can accept an electron pair. A number of nucleophilic substitution reactions can occur with alkyl halides, alcohols and epoxides. However, it can also take place with carboxylic acid derivatives, and is called nucleophilic acyl substitution. 

Preparation of amides Ammonia, 1° and 2° amines react with carboxylic acids to produce, respectively, 1°, 2° and 3° amides, through a nucleophilic acyl substitution reaction. The reaction of ammonia and a carhoxylic acid initially forms a carhoxylate anion and an ammonium cation. Normally the... 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

Carboxylic acids react under Pfitzner-Moffatt conditions, resulting in the formation of methylthiomethyl esters and /V-acylureas.41 Nevertheless, although the authors are not aware of any report involving the selective oxidation of alcohols in the presence of a carboxylic acid, such outcome would be likely with carboxylic acids with little nucleophilicity, as standard Pfitzner-Moffatt oxidations are performed in the presence of trifluoroacetate that is known for not to interfere. 

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