REACTION OF CARBOXYLATE SALTS

When carboxylate salts react with acid halogens or their solutions, carboxylic acids are formed. 

Write equations for the transformations below indicating conditions and catalysts. 

SOME COMMON CARBOXYLIC ACIDS 6.1. FORMIC ACID 

Formic acid is the simplest carboxylic acid (HCOOH). 

In nature, it is found in the stings and bites of many insects, including bees and ants. The name formic is derived from the Latin name for ant, formica. 

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Especially for large-scale work, esters may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents45 or with crown ether catalysts.46 The reactivity order for carboxylate salts is Na+ < K+ < Rb+ < Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due to both high solubility and minimal ion pairing with the anion 47 Acetone is a good solvent for reaction of carboxylate anions with alkyl iodides48 Cesium fluoride in DMF is another useful... 

As noted in the preceding section, one of the most general methods of synthesis of esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid derivative. Section 3.2.5 dealt with two other important methods, namely, reactions with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate esters. There is also the acid-catalyzed reaction of carboxylic acids with alcohols, which is called the Fischer esterification. 

Reaction of carboxylate salts with chloromethyl ethers (ROCH2CI) takes place under conditions similarly used to protect hydroxyl functions [Scheme 6.82].186 In the absence of acid, the resultant acetal esters display reactivity typical of alky esters. 

A second method of ester preparation involves the reaction of carboxylate salts with alkyl halides, sulfates, or sulfonates. Because carboxylate ions are relatively weak nucleophiles in protic solvents, this reaction is too slow to be convenient under many circumstances. Use of solvents such as dimethyl sulfoxide and hexamethylphosphoramide, however, which selectively activate anionic nucleophiles, results in much-improved reaction rates. Reaction of carboxylate salts with halides has been found to be a satisfactory preparative reaction in these solvents. The procedure has been found to be particularly useful for certain hindered acids. Scheme 5.4 lists some... 

Especially for large-scale work, esters may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl bromides, iodides or tosylates. The carboxylate anion is not a particularly reactive nucleophile so reaction proceeds best in polar aprotic solvents or with crown ether catalysis. Acetone has also been found to be a good solvent for reactions with alkyl iodides. Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters which can be relatively difficult to prepare by the acid-catalyzed esterification reactions to be discussed in Section 3.4. Sections F and G of Scheme 3.2 give some specific examples of ester alkylation by both diazoalkanes and other alkylating agents. 

Reaction of carboxylate salt with acid chloride (20.11)... 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

Reaction of carboxylate ion with nitrophenyl sulfites gives the carboxylate -nitrophenyl esters. If the -nitrophenyl sulfite is unsymmethcal (02NCgH40S(0)0R, where R is ethyl or phenyl), carboxylate attacks the -nitrophenyl side (69). Some amino acids react with methyl and benzyl sulfites in the presence of -toluenesulfonic acid to give methyl and benzyl esters of the amino acids as -toluenesulfonate salts (70). With alcohols, the conversion of henzil to a monoacetal upon addition of sulfuric acid to the henzil in methanol and dimethyl sulfite proceeds in high yield (71). 

Reactant and product structures. Because the transition state stmcture is normally different from but intermediate to those of the initial and final states, it is evident that the stmctures of the reactants and products should be known. One should, however, be aware of a possible source of misinterpretation. Suppose the products generated in the reaction of kinetic interest undergo conversion, on a time scale fast relative to the experimental manipulations, to thermodynamically more stable substances then the observed products will not be the actual products of the reaction. In this case the products are said to be under thermodynamic control rather than kinetic control. A possible example has been given in the earlier description of the reaction of hydroxide ion with ester, when it seems likely that the products are the carboxylic acid and the alkoxide ion, which, however, are transformed in accordance with the relative acidities of carboxylic acids and alcohols into the isolated products of carboxylate salt and alcohol. 

It has been shown that reaction of carboxylic acids with benzyl halides, which does not occur when heated conventionally, could be performed efficiently under the action of MW irradiation in the presence of a quaternary ammonium salt as a catalyst (Eq. 3) [15]. Typical results are given in Tab. 5.3. 

PP Pfeffer, LS Silbert. Esterification by alkylation of carboxylate salts. Influence of steric factors and other parameters on reaction rates. J Org Chem 41, 1373, 1976. 

Miscellaneous Reactions.—A full report has appeared of the reactions of carbon dioxide and carbon disulphide with tervalent phosphorus aryl esters and amines the products are ureas and thioureas, respectively.74 The suggested mechanism, previously invoked for similar reactions of carboxylic acids, involves the N-phosphonium salt (97). 

An extension of the Barbier reaction to carboxylates salts [90] affords a simple access to furanyl ketones [91]. By sonication of a mixture of a lithium carboxylate, an alkyl chloride and lithium in THE at room temperature, the intermediate organolithium reagent forms rapidly, then generates the 2-furanyl lithium which adds to the carboxylate group in high yields. The method constitutes an example of a reaction cascade , in which several intermediates are generated sequentially (Scheme 3.13). 

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. 

The reaction of sodium salt of carboxylic acid (sodium formate) with acid chloride. 

Similar to inorganic acids, the reaction of carboxylic acids and bases produces carboxylic acid salts. Several of these salts are commonly used in foods and beverages as preservatives. The most common are salts from benzoic, propionic, and sorbic acids. The salts of these acids have names ending with ate, and can often be found in the list of ingredients of baked goods and fruit drinks. Several common preservatives are shown in Figure 15.11. 

The analysis of polymeric and gaseous products of the reaction of PMMA and di-methylamine at low dimethylamine levels shows that there was a clean reaction that produced 1 eq of anhydride (NOT Amide) per 1 eq of dimethylamine and per 1 eq of MMA. Note that this is in most close agreement with pathway 2a- 3a (Figure 2) in which most of the MMA carbonyls have been converted to COOH or alkylammonium COO salts followed by closure to anhydride. This shows that direct acyl addition (2c— 3c) to form amide, or reaction of carboxylate with adjacent ester (2b- 3b) to form anhydride (which liberates MeOH after proton transfer, and requires only 0.5 eq. dimethylamine per MMA group) are not the predominant pathways under these conditions. The Flory limit effect is consistent with random initial MAA formation, which after cyclization to anhydride (Figure 2) eventually leads to some groups trapped between rings which remain in the uncyclized acid form. 

Typical synthetic procedures include the reaction of alkyl halides with the silver salts of carboxylic acids, the reaction of carboxylate anions in alkali with an excess of a dialkyl sulphate, (especially dimethyl sulphate), and heating tertiary184 or quaternary ammonium salts of carboxylic acids. These routes are particularly valuable for the preparation of esters of seriously sterically hindered acids. For example, Fuson et al.iK made the methyl ester of 2,4,6-triethylbenzoic acid by heating the tetramethyl ammonium salt to 200-250°C, viz. 

Acyl chlorides. Acyl chlorides are formed rapidly by reaction of carboxylic acids with SOCl2 and pyridine in CH2C12 at 25°. The dicyclohexylammonium salts of carboxylic acids react particularly rapidly (ca. 1 minute). The acid chlorides prepared in situ in this way react with amines in the presence of DMAP or DBU to form amides in >85% yield. This SOCl2-Py method is also useful for peptide synthesis with slight racemization. 

Adipic acid undergoes the usual reactions of carboxylic acids, including esterification, amidation, reduction, halogenation, salt formation, and dehydration. Because of its bifunclionai nature, il also undergoes several industrially significant polymerization reactions. 

In their study on the automation of the derivatization reaction of carboxylic acids, Wolf and Korf (34) chose bromomethylmethoxycoumarin (Br-MMC) as a label because of its commercial availability. The automation of this reaction is problematic, because elevated temperatures are required in the manual procedures and the reaction had to take place in an aprotic environment. The addition of a solid salt also complicates the procedure. They describe a solution to this problem using a suspension of potassium carbonate and appropriate reagent concentrations. The samples were detected by a fluorescence detector equipped with a 5-ju.l cell, using an excitation wavelength of 325 nm and a cutoff filter of 398 nm. 

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