Alcohols by Fischer esterification

Section 20.7 Esters occur naturally or are prepared from alcohols by Fischer esterification or by acylation with acyl chlorides or acid anhydrides (see Table 20.3). 

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). 

With a secure route to pentacyclic amine 2, the completion of the total synthesis of 1 requires only a few functional group manipulations. When a solution of 2 in ethanol is exposed to Pd-C in an atmosphere of hydrogen, the isopropenyl double bond is saturated. When a small quantity of HCI is added to this mixture, the hydro-genolysis of the benzyl ether is accelerated dramatically, giving alcohol 15 in a yield of 96%. Oxidation of the primary alcohol in 15 with an excess of Jones reagent, followed by Fischer esterification, gives ( )-methyl homosecodaphniphyllate [( )-1] in an overall yield of 85 % from 2. 

What carboxylic acid and alcohol are needed to prepare each ester by Fischer esterification ... 

Prepare methyl ester (a) by Fischer esterification (Section 13.6) of phenylacetic acid with methanol.Then treat this ester with ammonia to prepare amide (b). Alternatively, treat phenylacetic acid with thionyl chloride (Section 13.7) to give an acid chloride, and then treat the acid chloride with two equivalents of ammonia to give amide (b). Reduction of amide (b) by LiAIH4 gives the 1 ° amine (c). Similar reduction of either phenylacetic acid or ester (a) gives 1 ° alcohol (d) ... 

Esters cannot be prepared from tertiary alcohols using the Fischer esterification method because these alcohols tend to dehydrate under acid conditions. Esters of phenols also cannot be prepared by Fischer esterification because the equihbrium constant for the reaction is about 10". ... 

We recall that esters of alcohols can be prepared by Fischer esterification (Section 20.12). Esters of phenols cannot be prepared by this method because the equilibrium constant is not favorable. However, acid chlorides react with of both alcohols and phenols to give esters. The reaction produces HCl, and pyridine is added to the reaction mixture to neutralize the HCl. 

Fischer esterification is reversible and the position of equilibrium lies slightly to the side of products when the reactants are simple alcohols and carboxylic acids When the Fis cher esterification is used for preparative purposes the position of equilibrium can be made more favorable by using either the alcohol or the carboxylic acid m excess In the following example m which an excess of the alcohol was employed the yield indicated IS based on the carboxylic acid as the limiting reactant... 

Although the term ester, used without a modifier, is normally taken to mean an ester of a car boxylic acid, alcohols can react with inorganic acids in a process similar- to the Fischer esterification. The products are esters of inorganic acids. For example, alkyl nitrates are esters formed by the reaction of alcohols with nitric acid. 

Normal Fischer esterification of tertiary alcohols is unsatisfactory because the acid catalyst required causes dehydration or rearrangement of the tertiary substrate. Moreover, reactions with acid chlorides or anhydrides are also of limited value for similar reasons. However, treatment of acetic anhydride with calcium carbide (or calcium hydride) followed by addition of the dry tertiary alcohol gives the desired acetate in good yield. 

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need to use an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. 

The net effect of Fischer esterification is substitution of an -OH group by —OR. Aii steps are reversible, and the reaction can be driven in either direction by choice of reaction conditions. Ester formation is favored when a large excess of alcohol is used as solvent, but carboxylic acid formation is favored when a large excess of water is present. 

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). The ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid (Figure 21.8). Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, Figure 21.8 is the reverse of Figure 21.4. 

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. 

Tanaka and Kakiuchi (6) proposed catalyst activation via a hydrogen donor such as an alcohol as a refinement to the mechanism discussed by Fischer (7) for anhydride cured epoxies in the presence of a tertiary amine. The basic catalyst eliminates esterification reactions (8). Shechter and Wynstra ( ) further observed that at reaction conditions BDMA does not produce a homopolymerization of oxiranes. 

This method is called the Fischer esterification. It s a condensation reaction where the loss of a water molecule accompanies the joining of the alcohol portion to the acid portion. The acid gives up the OH and the alcohol gives up the H to make the water molecule. All steps in the mechanism are reversible (that is, it establishes an equilibrium), so removing the ester as soon as it forms is helpful. Removal of the ester is normally easy since esters typically have lower boiling points than alcohols and carboxylic acids. Figure 12-20 illustrates the mechanism for the acid-catalyzed formation of an ester by the reaction of an alcohol with a Ccirboxylic acid. 

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). 

Preparation of esters Esters are obtained by refluxing the parent carboxylic acid and an alcohol with an acid catalyst. The equilibrium can be driven to completion by using an excess of the alcohol, or by removing the water as it forms. This is known as 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 [IS] (equation 10) Owing to the strong acidity of a fluonnated carboxylic acids, Fischer esterification with most aliphatic alcohols proceeds autocatalytically [79 20]... 

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. 

Alcohols can be converted to esters by means of the Fischer Esterification Process. In this method, an alcohol is reacted with a carboxylic acid in the presence of an inorganic acid catalyst. 

The Fischer esterification proceeds via a carbocation mechanism. In this mechanism, an alcohol is added to a carboxylic acid by the following steps ... 

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. 

This reaction, known as Fischer esterification, requires the presence of an acid catalyst. Because the carboxylic acid and the ester have similar reactivities, the reaction is useful only if a method can be found to drive the equilibrium in the direction of the desired product—the ester. In accord with Le Chatelier s principle, this is accomplished by using an excess of one of the reactants or by removing one of the products. An excess of the alcohol is used if it is readily available, as is the case for methanol or ethanol. Or water can be removed by azeotropic distillation with a solvent such as toluene. 

The Fischer esterification converts carboxylic acids and alcohols directly to esters by an acid-catalyzed nucleophilic acyl substitution. The net reaction is replacement of the acid —OH group by the —OR group of the alcohol. 

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