Carboxylic acid esters reactivity with nucleophiles

Reductive carbonylation of 1,1-dibromocyclopropanes with tetracarbonylnickel in dimethyl-formamide in the presence of a nucleophile is a powerful method for direct introduction of carboxylic acid functions to cyclopropanes. Nucleophiles, such as alcohols, amines, and silylamines, are particularly reactive and give cyclopropyl esters and amides, respectively, in reasonable to good yields, e.g. formation of 5 and... 

The electrophilic reactivity of the carbonyl carbon in carboxylic acid derivatives is weakened by good electron-donating substituents. This effect, measurable by IR spectroscopy, is responsible not only for the decrease in the reactivity with nucleophiles and acid, but also for the increased basicity along the series acyl habdes-anhydrides-esters-amides. Electron donation by resonance from the nitrogen in amides is so pronounced that there is hindered rotation about the amide bond on the NMR time scale. 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

The effect of a carboxy group is illustrated by the reactivity of 2-bromopyridine-3- and 6-carboxylic acids (resonance and inductive activation, respectively) (cf. 166) to aqueous acid under conditions which do not give hydroxy-debromination of 2-bromopyridine and also by the hydroxy-dechlorination of 3-chloropyridine-4-car-boxylic acid. The intervention of intermolecular bifunctional autocatalysis by the carboxy group (cf. 237) is quite possible. In the amino-dechlorination (80°, 4 hr, petroleum ether) of 5-carbethoxy-4-chloropyrimidine there is opportunity for built-in solvation (167) in addition to electronic activation. This effect of the carboxylate ion, ester, and acid and its variation with charge on the nucleophile are discussed in Sections I,D,2,a, I,D,2,b, and II,B, 1. A 5-amidino group activates 2-methylsulfonylpyridine toward methanolic am-... 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Two alternatives to conventional acid/base hydrolyses for cleaving esters are Sn2 displacement of the carboxylate group by reactive nucleophiles and nucleophilic attack at the carbonyl carbon. In this latter context we investigated the reaction of S-b-MM with potassium trimethylsilanolate, a so-called potassium superoxide equivalent (15). One advantage that this reagent has over potassium... 

Carboxylic acids may be covalently modified with adipic acid dihydrazide or carbohydrazide to yield stable imide bonds with extending terminal hydrazide groups. Hydrazide functionalities don t spontaneously react with carboxylate groups the way they do with aldehyde groups (Section 4.5, this chapter). In this case, the carboxylic acid first must be activated with another compound that makes it reactive toward nucleophiles. In organic solutions, this may be accomplished by using a water-insoluble carbodiimide (Chapter 3, Section 1.4) or by creating an intermediate active ester, such as an NHS ester (Chapter 2, Section 1.4). 

Acid chlorides are the most reactive carboxylic acid derivatives, and easily converted to acid anhydrides, esters and amides via nucleophilic acyl substitutions (see Section 5.5.5). Acid chlorides are sufficiently reactive with H2O, and quite readily hydrolysed to carboxylic acid (see Section 5.6.1). 

The reactivity of other nucleophiles is also of unusual interest. For example, F reacts efficiently with methyl esters of carboxylic acids without (3-hydrogens along an SN2 pathway (59) (Takashima and Riveros, 1978) to... 

A second method to efficientiy produce mediyl esters of carboxylic acids is to heat die acid with potassium carbonate and mediyl iodide. The mediyl ester is produced under mild conditions and is easily separated from die reaction byproducts. This method is somewhat different in tiiat die ester is formed by a nucleophilic displacement of iodide by die carboxylate ion. Normally carboxy-lates are not thought of as good nucleophiles—and tiiey are not—but mediyl iodide is a quite reactive electrophile which matches die poor nucleophilicity of die carboxylate satisfactorily. 

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