Carboxylic acids, esterification reactions

This procedure provides a convenient method for the esterification ol a wide variety of carboxylic acids. The reaction proceeds smoothly with sterically hindered acids6 and with acids which contain various functional groups. Esters are obtained in high purity using Kugelrohr distillation as the sole purification technique. In cases where traces of dichloromethane present no problems, the crude product is usually pure enough to be used directly in subsequent reactions. Methyl and ethyl ethers of phenols may also be prepared by this procedure (see Note 8). 

Although the ability of microwaves (MW) to heat water and other polar materials has been known for half a century or more, it was not until 1986 that two groups of researchers independently reported the application of MW heating to organic synthesis. Gedye et al. [1] found that several organic reactions in polar solvents could be performed rapidly and conveniently in closed Teflon vessels in a domestic MW oven. These reactions included the hydrolysis of amides and esters to carboxylic acids, esterification of carboxylic acids with alcohols, oxidation of alkyl benzenes to aromatic carboxylic acids and the conversion of alkyl halides to ethers. 

The combination of carboxyl activation by a carbodiimide and catalysis by DMAP provides a useful method for in situ activation of carboxylic acids for reaction with alcohols.10 The reaction proceeds at room temperature. Carbodiimides are widely applied in the synthesis of polypeptides from amino acids. The proposed mechanism for this esterification reaction involves activation of the acid via isourea 28 followed by reaction with another acid molecule to form anhydride... 

From the reaction between alcohols and carboxylic acids, esters and water are produced. This is called esterification. In this reaction, the hydrogen atom from the — OH group of an alcohol is replaced by the acyl group from a carboxylic acid. These reactions occur in the presence of strong acid catalysts such as HC1 or H2S04. 

Alvaro, M., Corma, A., Das, D., Fomes, V., and Garda, H. 2005. "Nafion"-functionalized mesoporous MCM-41 silica shows high activity and selectivity for carboxylic acid esterification and Friedel-Crafts acylation reactions. 7. Catal. 231 48-55. 

Esterification. Carboxylic acids react with (1) in CHCI3 or acetonitrile in the presence of 1 eq. of triethylamine to form an active ester (2), which can be isolated if desired. The esters (2) react with an alcohol, again in the presence of 1 eq. of base, to form an ester of the carboxylic acid. The reaction can be carried out in one step by mixing the acid, the alcohol, the coupling reagent, and 2 eq. of base in ether. In either case, the reaction takes place at 20°. Yields are generally in the range of 65-85%. 

As a source of HCHO, formalin, a 37 percent aqueous solution of HCHO stabilized with 12 to 15 percent of methanol, is the most popular. Besides formalin, paraformaldehyde [(HCHO) ] and trioxane [(HCHO)3] are also used. When methanol is added in the feed or when methylal [CH2(OCH3)2] or hemiformal [CH3OCH2 OH] is used as the source of HCHO, a mixture of carboxylic acids and esters is obtained because both the esterification of carboxylic acid and the hydrolysis of ester are much more rapid than the condensation reaction. The reaction is usually performed in the presence of an excess of carboxylic acid with respect to the amount of HCHO the carboxylic acid/HCHO molar ratio is 1.3 to 20 because HCHO is generally more susceptible to degradation than carboxylic acids. The reaction temperature is in the range of 250 to 400 °C. 

Acylation can be effected by direct esterification with carboxylic acids. The reaction is performed with activating agents and a base, with A,A-dicyclohexylcarbodii-mide (DCC) serving as a powerful condensation agent. The homogeneous-phase... 

Esters can be prepared by acid-catalyzed esterification or by reaction of the acid chloride with the alcohol. In small-scale syntheses, it is often more convenient to prepare the ester by reaction of the carboxylic acid with the appropriate diazo compound. Diazomethane is routinely used for making methyl esters, but more highly substituted esters can be prepared if the corresponding diazo compound is available. Benzhydryl esters, for example, are readily prepared from carboxylic acids by reaction with diphenyldiazomethane ... 

The 8-parameter was used with good results in structure-activity correlations for modeling the acid-catalyzed carboxylic acid esterification and ester hydrolysis, and bimolecular substitution reactions (Chiriac et al. 1996). 

Which method would you choose if you wanted to prepare cyclohexyl benzoate—Fischer esterification of the carboxylic acid or reaction of the acid chloride with an alcohol Explain. 

Ammonium hexanitratocerate(IV) is an efficient catalyst for fast esterification of carboxylic acids and alcohols under mild conditions (Goswami and Chowdhury, 2000). The reaction can be carried out under solventless conditions, or in chloroform. The reaction works with primary and secondary alcohols, and with aliphatic carboxylic acids. No reaction was observed for tertiary alcohols or for aromatic acids. The method is of interest because it is also applicable to the esterification of alcohols based on steroids and on other natural products (scheme 37). Pan and coworkers described the esterification of phenylacetic acids and cis-o cic acid with simple primary and secondary alcohols in presence of an excess of CAN at room temperature (Pan et al., 2003). The alcohol acted as solvent. Ammonium hexanitratocerate(IV) does catalyze not only the esterification of carboxylic acid, but also the transesterification with another alcohol (Stefane et al., 2002). 

The data obtained from isotopic labeling studies and several other observations have clearly established the mechanism of the acid-catalyzed esterification of carboxylic acids. The reaction occurs in four steps. 

Other Condensation Reactions. BF3-MeOH and BF3-OEt2 with ethanol are widely used in the esterification of various kinds of aliphatic, aromatic, and carboxylic acids the reaction is mild, and no rearrangement of double bonds occurs. This esterification is used routinely for stable acids prior to GLC analysis. Heterocyclic carboxylic acids, unsaturated organic acids, biphenyl-4,4 -dicarboxylic acid, 4-aminobenzoic acid, and the very sensitive 1,4-dihydrobenzoic acid are esterified directly. 

List [86] and Jorgensen [87] have recently independently described a novel application of L-proline (107) for catalysis of enantioselective hydrazidation of aldehydes [88]. For example, when aldehyde 106 is allowed to react with di-tert-butyl azodicarboxylate (95) in the presence of 10 mol% 107, adduct 108 is isolated in > 90% yield and 93% ee (Scheme 10.18) [87]. The product hydra-zides can be transformed into protected amino acid derivatives through a sequence that involves oxidation of the aldehyde to the corresponding carboxylic acid, esterification, deprotection, and N-N bond cleavage with Raney-Ni [86, 87]. The observed selectivity has been attributed to the intervention of transition state 111 [86]. This structure incorporates a hydrogen bond between proline s carboxyl group and the azodicarboxylate as a key organizing feature. The transition state structure has parallels to that proposed for the proline-cata-lyzed aldol addition reactions and is supported by quantum mechanical studies by Houk [89]. 

Oxidation of the primary alcohol gives the corresponding carboxylic acid (A). Reaction of A with thionyl chloride converts the carboxylic acid to the acid chloride (B). Reaction of B with excess ammonia produces the amide (C). Carboxylic acid (A) undergoes Fischer esterification upon reaction with ethanol and catalytic acid to produce the ethyl ester (D). Reaction of acid chloride B with a lithium trialkoxyalumimrm hydride produces aldehyde F, which can also be made from ester D by reaction with DIBAH (E). 

Although the term ester used without a modifier is normally taken to mean an ester of a carboxylic acid alcohols can react with inorganic acids m a process similar to the Fis cher esterification The products are esters of inorganic acids For example alkyl nitrates are esters formed by the reaction of alcohols with nitric acid... 

The most apparent chemical property of carboxylic acids their acidity has already been examined m earlier sections of this chapter Three reactions of carboxylic acids—con version to acyl chlorides reduction and esterification—have been encountered m pre vious chapters and are reviewed m Table 19 5 Acid catalyzed esterification of carboxylic acids IS one of the fundamental reactions of organic chemistry and this portion of the chapter begins with an examination of the mechanism by which it occurs Later m Sec tions 19 16 and 19 17 two new reactions of carboxylic acids that are of synthetic value will be described... 

Section 27 5 Ammo acids undergo reactions characteristic of the ammo group (e g amide formation) and the carboxyl group (e g esterification) Ammo acid side chains undergo reactions characteristic of the functional groups they contain... 

One of the most sensitive tests of the dependence of chemical reactivity on the size of the reacting molecules is the comparison of the rates of reaction for compounds which are members of a homologous series with different chain lengths. Studies by Flory and others on the rates of esterification and saponification of esters were the first investigations conducted to clarify the dependence of reactivity on molecular size. The rate constants for these reactions are observed to converge quite rapidly to a constant value which is independent of molecular size, after an initial dependence on molecular size for small molecules. The effect is reminiscent of the discussion on the uniqueness of end groups in connection with Example 1.1. In the esterification of carboxylic acids, for example, the rate constants are different for acetic, propionic, and butyric acids, but constant for carboxyUc acids with 4-18 carbon atoms. This observation on nonpolymeric compounds has been generalized to apply to polymerization reactions as well. The latter are subject to several complications which are not involved in the study of simple model compounds, but when these complications are properly considered, the independence of reactivity on molecular size has been repeatedly verified. 

Process Applications The production of esters from alcohols and carboxylic acids illustrates many of the principles of reactive distillation as applied to equilibrium-limited systems. The equilibrium constants for esterification reactions are usually relatively close to unity. Large excesses of alcohols must be used to obtain acceptable yields with large recycles. In a reactive-distiUation scheme, the reac-... 

Chirazymes. These are commercially available enzymes e.g. lipases, esterases, that can be used for the preparation of a variety of optically active carboxylic acids, alcohols and amines. They can cause regio and stereospecific hydrolysis and do not require cofactors. Some can be used also for esterification or transesterification in neat organic solvents. The proteases, amidases and oxidases are obtained from bacteria or fungi, whereas esterases are from pig liver and thermophilic bacteria. For preparative work the enzymes are covalently bound to a carrier and do not therefore contaminate the reaction products. Chirazymes are available form Roche Molecular Biochemicals and are used without further purification. 

Esterification (Section 15.8) In the presence of an acid catalyst, carboxylic acids and alcohols react to form esters. The reaction is an equilibrium process but can be driven to favor the ester by removing the water that is formed. 

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