Esters from carboxylic acids Fischer

Allyl-based protecting groups have become a popular choice for the protection of carboxylic acids, especially in peptide and glycopeptide synthesis. Formation of allyl esters from carboxylic acids has typically been carried out using allyl alcohol/DCC/DMAP,f i allyl bromide/Cs2C03,f and Fischer esterification conditions. Additionally, methyl and ethyl esters have been transesterified to allyl esters using NaH, DBU/LiBr, and Ti(Oi-Pr)4 as catalysts.f" " " ... 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

From carboxylic acids (Sections 15 8 and 19 14) In the pres ence of an acid catalyst alco hols and carboxylic acids react to form an ester and water This IS the Fischer esterification... 

For most cases, common fluoroacyl derivatives are sufficiently reactive and selective Thus conversion of perfluoroglutaric dichloride to a monomethyl ester by methanol proceeds smoothly under the appropriate reaction conditions [17] (equation 9) Perfluorosuccinic acid monoester fluoride, on the other hand, is prepared most conveniently from perfluorobutyrolacetone (equation 10) Owing to the strong acidity of a fluorinated carboxylic acids, Fischer esten-ficaiton with most aliphatic alcohols proceeds autocatalytically [79 20]... 

Esters are usually prepared from carboxylic acids by the methods already discussed. Thus, carboxylic acids are converted directly into esters by SK2 reaction of a carboxyfate ion with a primary alkyl halide or by Fischer esterification of a carboxylic acid with an alcohol in the presence of a mineral acid catalyst. In addition, acid chlorides are converted into esters by treatment with an alcohol in the presence of base (Section 21.4). 

Current interest in synthetic fuels production by Fischer-Tropsch (FT) reactions have created a need for removal of byproduct oxygenates, formed by the FT reaction. The oxygenates consist of primary and internal alcohols, aldehydes, ketones, esters and carboxylic acids. The hydrocarbon products derived from the FT reaction range from methane to high molecular weight paraffin waxes containing more than 50 carbon atoms. 

The most important reactions of carboxylic acids are the conversions to various carboxylic acid derivatives, e.g. acid chlorides, acid anhydrides and esters. Esters are prepared by the reaction of carboxylic acids and alcohols. The reaction is acid catalysed and is known as Fischer esterification (see Section 5.5.5). Acid chlorides are obtained from carboxylic acids by the treatment of thionyl chloride (SOCI2) or oxalyl chloride [(COCl)2], and acid anhydrides are produced from two carboxylic acids. A summary of the conversion of carboxylic acid is presented here. All these conversions involve nucleophilic acyl substitutions (see Section 5.5.5). 

While still useful for large-scale esterification of fairly robust carboxylic acids, Fischer esterification is generally not useful in small-scale reactions because the esterification depends on an acid-catalyzed equilibrium to produce the ester. The equilibrium is usually shifted to the side of the products by adding an excess of one of the reactants—usually the alcohol—and refluxing until equilibrium is established, typically several hours. The reaction is then quenched with base to freeze the equilibrium and the ester product is separated from the excess alcohol and any unreacted acid. This separation is easily accomplished on a large scale where distillation is often used to separate the product from the by-products. For small-scale reactions where distillation is not a viable option, the separation is often difficult or tedious. Consequently Fischer esterification is not widely used for ester formation in small-scale laboratory situations. In contrast, intramolecular Fischer esterification is very effective on a small scale for the closure of hydroxy acids to lactones. Here the equilibrium is driven by tire removal of water and no other reagents are needed. Moreover the closure is favored entropically and proceeds easily. 

Fingerprint region (Section 13 20) The region 1400-625 cm of an infrared spectrum This region is less character istic of functional groups than others but varies so much from one molecule to another that it can be used to deter mine whether two substances are identical or not Fischer esterification (Sections 15 8 and 19 14) Acid cat alyzed ester formation between an alcohol and a carboxylic acid... 

Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4//-pyrido-[l,2-u]pyrimidin-4-ones 289 by heating in 85% phosphoric acid, or in PPA yielded 7,12-dihydropyrimido[l, 2 l,2]pyrido[3,4-Z)]indol-4(6//)-ones 290 (96JHC799, 99MI12, 00MI22). From the 3-ester and 3-carboxylic acid derivatives 289 (R = COOEt, COOH) and decarboxylated products 290 (R = H) were obtained. 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

Interestingly, the Fischer indole synthesis does not easily proceed from acetaldehyde to afford indole. Usually, indole-2-carboxylic acid is prepared from phenylhydrazine with a pyruvate ester followed by hydrolysis. Traditional methods for decarboxylation of indole-2-carboxylic acid to form indole are not environmentally benign. They include pyrolysis or heating with copper-bronze powder, copper(I) chloride, copper chromite, copper acetate or copper(II) oxide, in for example, heat-transfer oils, glycerol, quinoline or 2-benzylpyridine. Decomposition of the product during lengthy thermolysis or purification affects the yields. 

It was also synthesised by E. Fischer in 1901 from 7-phthalimido-propylmalonic ester which he employed in the preparation of ornithine. The bromine derivative of this compound when treated with ammonia gave a complex mixture of products which after hydrolysis by hydrochloric acid at 100° C. gave phthalimide and a-pyrrolidine carboxylic acid —... 

Esters, RC02R, are named as salts are the R group is named first, followed by the name of the carboxylate group (for example, CH3CO2CH2CH3 is ethyl acetate). Esters can be prepared from an acid and an alcohol, with a mineral acid catalyst (Fischer esterification). The key step of the mechanism is nucleophilic attack by the alcohol on the protonated carbonyl group of the acid. Many esters are used as flavors and perfumes. 

Fig. 6. 22. Aa[2 mechanism of the acid-catalyzed hydrolysis of carboxylic esters (read from left to right) Aa[2 mechanism of the Fischer esterification of carboxylic acids (read from right to left). H means migration of a proton.

The mechanism for the Fischer esterification is shown in Figure 19.3. Sulfuric acid, hydrochloric acid, orp-toluenesulfonic acid is most often used as a catalyst. The mechanism will be easier to remember if you note the similarities to other acid-catalyzed mechanisms, such as the one for the formation of acetals in Figure 18.5. Also note that the steps leading from the tetrahedral intermediate to the carboxylic acid and alcohol starting materials and to the ester and water products are very similar. 

Amino acids exhibit chemical reactions that are typical of both amines and carboxylic acids. For example, the acid can be converted to an ester by the Fischer method. This reaction requires the use of an excess of acid because one equivalent is needed to react with the amino group of the product. As another example, the amine can be converted to an amide by reaction with acetic anhydride. Additional examples are provided by the reactions that are used in the preparation of peptides from amino acids described in Section 26.7 ... 

Trimethylbenzoic acid has two methyl groups ortho to the carboxylic acid functional group. These bulky methyl groups block the approach of the alcohol and prevent esterification from occurring under Fischer esterification conditions. A possible route to the methyl ester ... 

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