Carboxylic acids reactivity with nucleophiles

As one of the most reactive groups of carboxylic acid derivatives, acyl halides are very useful substrates for the preparation of the other classes of derivatives. For example, anhydrides may be synthesized by the reaction of carboxylic acid salts with an acyl halide. In this reaction, the carboxylate anion acts as the nucleophile, eventually displacing the halide leaving group. 

Carboxylic acid derivatives undergo nucleophilic substitution whereas aldehydes and ketones undergo nucleophilic addition. This is because nucleophilic substitution of a ketone or an aldehyde would generate a carbanion or a hydride ion respectively (Following fig.). These ions are unstable and highly reactive, so they are only formed with difficulty. Furthermore, C-C and C-H o bonds are easily broken. Therefore, nucleophilic substitutions of aldehydes or ketones are not feasible. 

Once the carboxylic acid is deprotonated, substitutions are prevented because (almost) no nucleophile will attack the carboxylate anion. Under neutral conditions, alcohols are just not reactive enough to add to the carboxylic acid but, with add catalysis, esters can be formed from alcohols and carboxylic acids. 

This difference in chemical reactivity can be converted into a differential etch rate by treating the exposed film with an appropriate silylating reagent. For example, chlorotrimethylsilane, hexamethyldisilazane and bis(trimethylsilyl)acetamide are well know to react with phenolic hydroxyls, carboxylic acids and other nucleophilic species to form the corresponding trimethylsilyl derivatives. 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

Carbon dioxide and bicarbonate have very different chemical reactivities. CO2 is quite reactive toward nucleophiles (J), reacting, for example, with hydroxide to form bicarbonate, with ammonia and primary and secondary amines to form carbamates, with enolates to form carboxylic acids, and with a variety of organo-metallic compounds (e.g., Grignard reagents and organolithium reagents) to form carboxylic acid salts (i). Bicarbonate is much less reactive. 

Nucleophiles react with a, 8-unsaturated carboxylic acid derivatives with reactive carbonyl groups, such as acyl chlorides, to form nucleophilic acyl substitution products. Conjugate addition products are formed from the reaction of nucleophiles with less reactive carbonyl groups, such as ester and amides. 

Relative reactivities of carboxylic acid derivatives toward nucleophilic acyl substitution. A more reactive derivative may be converted to a less reactive derivative by treatment with an appropriate reagent. Treatment of a carboxylic acid with thionyl chloride converts the carboxylic acid to the more reactive acid chloride. Carboxylic acids are about as reactive as esters under acidic conditions, but are converted to the unreactive carboxylate anions under basic conditions. 

Grigat reported that the carbon atom of the -OCN group is strongly electrophilic. Thus cyanates, like isocyanates (-NC0) should be reactive with nucleophilic reagents under mild conditions. Cyanates do react with active hydrogen containing materials such as polyols, amines and carboxylic acids under fairly mild conditions. The adducts with active hydrogen co-reactants are chemically different than those obtained from isocyanates. These are termed imidocarbonates, isoureas, bis(imidocarbonate) imides, etc. 

Reaction of an a, -unsaturated carboxylic acid derivative with a nucleophile forms a nucleophilic addition-elimination product with a reactive carbonyl group and a conjugate addition product with a less reactive carbonyl group (Section 17.19). 

Relative Reactivities of Carboxylic Acid Derivatives in Nucleophilic Addition-Elimination with Water... 

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. 

We recall that amides are best made by the reaction of acid chlorides and amines. Therefore, polyamides can be made by reaction of a monomer with two acid chloride functional groups and a monomer with two amine groups. However, the high reactivity of acid chlorides with nucleophiles such as water requires special precautions to preserve this reagent. Thus, these compounds are not much used in industrial laboratories. An alternate method for the synthesis of amides is the direct heating of an amine with a carboxylic acid. The first product is an ammonium salt, which loses water when heated to form the amide. 

Rates of debromination of bromonitro-thiophenes and -selenophenes with sodium thio-phenoxide and sodium selenophenoxide have been studied. Selenophene compounds were about four times more reactive than the corresponding thiophene derivatives. The rate ratio was not significantly different whether attack was occurring at the a- or /3-position. As in benzenoid chemistry, numerous nucleophilic displacement reactions are found to be copper catalyzed. Illustrative of these reactions is the displacement of bromide from 3-bromothiophene-2-carboxylic acid and 3-bromothiophene-4-carboxylic acid by active methylene compounds (e.g. AcCH2C02Et) in the presence of copper and sodium ethoxide (Scheme 77) (75JCS(P1)1390). 

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. 

Like all anhydrides (Section 21.5), the mixed carboxylic-phosphoric anhydride is a reactive substrate in nucleophilic acyl (or phosphoryl) substitution reactions. Reaction of 1,3-bisphosphoglycerate with ADR occurs in step 7 by substitution on phosphorus, resulting in transfer of a phosphate group to ADP and giving ATP plus 3-phosphoglycerate. The process is catalyzed by phospho-gjvcerate kinase and requires Mg2+ as cofactor. Together, steps 6 and 7 accomplish the oxidation of an aldehyde to a carboxylic acid. 

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