Carboxylate ions, electrophilicity

Because under basic conditions carboxylic acids are deprotonated to the carboxylate ions, which are no longer electrophilic enough that a weak nucleophile like MeO- can attack them. Upon workup the carboxylate is neutralized to give back the carboxylic acid. 

The reactions enumerated lead to the adducts that are observable by means of the ESR method. In the cases of maleic and fumaric acids, ESR spectra can be recorded at high enough pH values only Being a strong electrophile, radical SO4 is more active toward a carboxylate ion than to neutral molecules of unsaturated acids. 

The nucleophiles that are used for synthetic purposes include water, alcohols, carboxylate ions, hydroperoxides, amines, and nitriles. After the addition step is complete, the mercury is usually reductively removed by sodium borohydride. The net result is the addition of hydrogen and the nucleophile to the alkene. The regioselectivity is excellent and is in the same sense as is observed for proton-initiated additions.16 Scheme 4.1 includes examples of these reactions. Electrophilic attack by mercuric ion can affect cyclization by intramolecular capture of a nucleophilic functional group, as illustrated by entries 9-11. Inclusion of triethylboron in the reduction has been found to improve yields (entry 9).17... 

The above mechanism assigns an electrophilic function to the metal ion. During decarboxylation, an electron pair initially associated with the carboxylate ion group is transferred to the rest of the molecule. A metal ion, because of its positive charge, should assist this transfer (46). 

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. 

Amides can be synthesized directly from carboxylic acids, using heat to drive off water and force the reaction to completion. The initial acid-base reaction of a carboxylic acid with an amine gives an ammonium carboxylate salt. The carboxylate ion is a poor electrophile, and the ammonium ion is not nucleophilic, so the reaction stops at this point. Heating this salt to well above 100 °C drives off steam and forms an amide. This direct synthesis is an important industrial process, and it often works well in the laboratory. 

Many reactions become possible only in such superbasic solutions, while others can be carried out under much milder conditions. Only some examples of preparative interest (which depend on the ionization of a C—H or N—H bond) will be mentioned here. The subsequent reaction of the resulting carbanion may involve electrophilic substitution, isomerization, elimination, or condensation [321, 322]. Systematic studies of solvent effects on intrinsic rate constants of proton-transfer reactions between carbon acids and carboxylate ions as well as amines as bases in various dimethyl sulfoxide/ water mixtures have been carried out by Bernasconi et al. [769]. 

The above considerations apply, also, to the calf-intestine enzyme, where the carboxylate ion (—COO ) will act as a nucleophilic center and the imidazolium group as an electrophile. According to Scheme 5, the intermediate enzyme-/S-D-galactoside compound will possess the nature of an ester. Evidently, Scheme 6 can apply equally well. It is not known, as yet, whether the large carbohydrate content of the most highly purified, calf-intestine /3-galactosidase is a part of the enzyme molecule or not. Nothing... 

Controlled addition of a suitable proton donor or electrophile (reductions) or nucleophile (oxidations) is often useful in determining a reaction mechanism. The strength of a proton donor may vary from perchloric acid through acetic acid and a phenol to an alcohol C acids, such as malonic ester, or N acids, such as urea, may also be used. Used as bases may be pyridine, carboxylate ions, alkoxides, or salts of malonic ester. Sometimes it is of interest to determine whether it is the basic or the nucleophilic properties of the compound that are important. The use of two bases with approximately the same pK values but widely differing in nucleophilicity, such as pyridine and a 2,6-dialkylpyridine, might answer the question. 

The term nucleophilicity refers to the relative rate of reaction of an electron donor with a given electrophile, as distinct from basicity, which refers to its relative affinity for a proton in an acid-base equilibrium. A quantitative relationship between rate and equilibrium constants was discovered by Brpnsted and Pedersen (1) in 1924. These authors found that the rate constants for the catalytic decomposition of nitramide by a family of bases, such as carboxylate ions (GCH2C02 ), could be linearly correlated with the acidities of their conjugate acids, pKHB. This observation led to the discovery of general base catalysis and the first linear free-energy relationship, which later became known as the Brpnsted equation ... 

From the results summarized in Table I, apparently the Brpnsted relationship will hold for all combinations of nucleophiles and electrophiles. Because, as pointed out previously, the Hammett equation is really a special case of the Brpnsted relationship, all the legion of nucleophile-electrophile, rate-equilibrium Hammett correlations that have been studied also fall under the scope of the Brpnsted relationship. For example, nucleophilicities of ArO , ArS , ArC(CN)2 , and the other families listed in footnote c of Table I have generally been correlated by the Hammett equation, where the acidities of benzoic acids in water are used as a model for substituent interactions with the reaction site (a), and the variable parameter p is used to define the sensitivity of the rate constants to these substituent effects. The Brpnsted equation (equation 3) offers a much more precise relationship of the same kind, because this equation does not depend on an arbitrary model and allows rate and equilibrium constants to be measured in the same solvent. Furthermore, the Brpnsted relationship is also applicable to families of aliphatic bases such as carboxylate ions (GCH2C02 ), alkoxide ions (GCH20 ), and amines (GCH2NH2). In addition, other correlations of a kinetic parameter (log fc, AGf, Ea, etc.) can be included with various thermodynamic parameters (pKfl, AG°, Eox, etc.) under the Brpnsted label. 

The mechanism for DCC coupling is not as complicated as it may seem. The carboxylate ion adds to the strongly electrophilic carbon of the diimide, giving an activated acyl derivative of the acid. This activated derivative reacts readily with the amine to give the amide, in the final step, DCU serves as an excellent leaving group. 

The alkoxide unit (C-0-) can transfer electrons back to the electrophilic carbon, but there are two leaving groups, as in previous cases. In 20, the leaving groups are OH and OiPr. Although it is not obvious, in water and with an excess of hydroxide ion, loss of OiPr (isopropoxide, in green) is more facile, and this generates the acid (acetic acid, 21). Because it is formed in the presence of hydroxide (isopropoxide is also present), the acid-base reaction leads to the final product of the first chemical step, carboxylate ion 22. To isolate acid 21, 22 is treated with aqueous acid as shown in the illustration, in a second chemical step. 

The less reactive, weak electrophilic azetidinium ions undergo ring-opening reactions with charged nucleophiles such as carboxyl ions. The reaction of PTHF with thiolane gives similar results (307). 

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