Esterification s.a. Carboxylic acid

Esterification (s. a. Carboxylic acid esters from carboxylic acids)... 

Fig. 9.16. Gentle esterification of a carboxylic acid II with DMF acetal (A upper part). The lower part gives an example of a chemoselective—since neither a cleavage of the substrate s Boc group nor a reaction on its stereocenter takes place—esterification according to the procedure discussed.

Esters are usually prepared from carboxylic acids by tlie methods already discussed. Thus, carboxylic acids are converted directly into esters bv S 2 reaction of a carboxylate ion with a primary alkyl halide or In- I ischer esterification of a carboxylic acid with an alcohol in the presence of a mineral acid catalyst. In addition, acid chlorides are converted into esters l y treatment with an alcohol in the presence of base (Section 21.4). 

Since the imidazolide method proceeds almost quantitatively, it has been used for the synthesis of isotopically labeled esters (see also Section 3.2), and it is always useful for the esterification of sensitive carboxylic acids, alcohols, and phenols under mild conditions. This advantage has been utilized in biochemistry for the study of transacylating enzymes. A number of enzymatic transacylations (e.g., those catalyzed by oc-chymo-trypsin) have been shown to proceed in two steps an acyl group is first transferred from the substrate to the enzyme to form an acyl enzyme, which is then deacylated in a second step. In this context it has been shown[21] that oc-chymotrypsin is rapidly and quantitatively acylated by Af-fraw.s-cinnamoylimidazole to give /ra/w-cinnamoyl-a-chymotrypsin, which can be isolated in preparative quantities and retains its enzymatic activity (see also Chapter 6). 

S Kim, JL Lee, YC Kim. A simple and mild esterification method for carboxylic acids using the mixed carboxylic-carbonic anhydrides. J Org Chem 50, 560, 1985. 

There are several examples of dehydrations of chemicals derived by renewable resources by use of heteregeneous catalytic approaches in the literature. These can be categorized into three types of reactions (a) reactions in which one (or more) molecule(s) of water is eliminated from a single substrate molecule, (b) reactions in which one (or more) molecule(s) of water is generated as the result of an esterification reaction between an alcohol and a carboxylic acid or carboxylic acid derivative and (c) reactions in which one (or more) molecule(s) of water is generated due to an etherification reaction between two alcohol functionalities. 

Most such esters have been made by primary synthesis (see Chapter 22) and some by esterification of corresponding carboxylic acids (see Section 28.1.2) or from halogeno-1,8-naphthyridines (see Section 24.2). A few extranuclear esters have been prepared by passenger alkylations. For example, by S-ethoxycarbonyla-tion as in Chapter 26. 

Most aliphatic acid.s enter the process easily, but more vigorous reaction conditions are necessary for aryl carboxylic acids or for sterically hindered alkanoic acids. Increased pressure can help counteract such problems, e.g. 2,2-dimethylpropanoic acid heated at 112°C in ethanol with o-phenylenediamine dihydrochloride for 24 h at 8kbar pressure gives a 48% yield of 2-l-butylbenzimidazolc 76. Care has to be taken, though, that the ethanol concentration is not too high, as esterification of the carboxylic acid becomes a competing reaction DMSO appears to be a suitable alternative... 

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 carboxylic acid. 

Vahteristo, K., S. Maury, A. Laaii, A. Solonen, H. Haario S. Koskimies (2009) Kinetics of Neopentyl Glycol Esterification with Different Carboxylic Acids. Industrial Engineering Chemistry Research, 48,6237-6247, ISSN 0888-5885. 

The mechanism for acid-catalyzed esterification of carboxylic acids is completely reversible, but is driven to the right (toward the ester product) but application of Le Chatelier s principle and removal of water (also see Chapter 18, Section 18.6.3). Another application of Le Chatelier s principle uses a large excess of the alcohol (butanol for the formation of 70) to shift the equilibrium toward the ester by increasing the probability that it will react with alcohol rather than with water. Note that if ester 70 is treated with an acid catalyst and water rather than butanol, the mechanism shown will convert the ester back to the acid. In other words, if water replaces butanol, the mechanism from 70 to 21 is that for acid-catalyzed hydrolysis of an ester to a carboxylic acid (Section 20.2). 

ACTIVE FIGURE 16.4 MECHANISM Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid. Co to this book s student companion site at www.cengage.com/chemistry/ mcmurry to expiore an interactive version of this figure. 

The design of a novel series of cycUn-dependent kinase (CDK) inhibitors with a macrocyclic quinoxaline-2-one 208 is reported (Kawanishi et al. 2006), where 208 was synthesized as shown in Scheme 5.50. The deprotonation of the fluorine-adjacent position of l-fluoro-2-iodobenzene 209, with LDA, followed by the carbon dioxide trapping and then esterification of the carboxylic acid, led to methyl 2-fluoro-3-iodobenzoate. The iodomagnesium exchange of methyl 2-fluoro-3-iodobenzoate according to Knochel s procedure (Knochel et al. 2003) followed by chloroglyoxylic acid ethyl ester resulted in ketoester 210, which was coupled with 3-[(tert-bulyldimethylsilyl)oxy]benzene-1,2-diamine to... 

Now let s draw the forward scheme. The starting alcohol is oxidized upon treatment with chromic acid (alternatively, PCC can be used for this step). The resulting ketone is then treated with molecular bromine (Br2) and sodium hydroxide, followed by aqueous acid, to give a carboxylic acid (via a haloform reaction). Finally, the carboxylic acid is treated with ethanol in the presence of an acid catalyst, giving the desired ester (via a Fischer esterification). 

In this definition ko is the rate constant for CH3COOR and k is the constant for RCOOR thus = 0 for R = CH3. Table 7-11 lists some values. Taft s Es steric constants are in some instances based on averages of several different reactions, so MacPhee et al. have defined a steric constant Es by Eq. (7-52) for a single reaction, namely, the acid-catalyzed esterification of carboxylic acids in methanol at 40°C. Es values are also given in Table 7-11. Additional Es and Es values are available. 

Methyl esters undergo trans-esterification with the quaternary ammonium salts at high temperature and the reaction has been used with some effect for the preparation of, for example, n-butyl esters by heating the methyl ester with tetra-n-butylammo-nium chloride at 140°C [31]. Optimum yields (>75%) are obtained in HMPA or in the absence of a solvent. A two-step (one-pot) trans-esterification under phase-transfer catalysed conditions in which the carboxylate anion generated by initially hydrolysis of the ester is alkylated has been reported for Schiff s bases of a-amino acids [32] and for A-alkoxycarbonylmethyl [1-lactams [33]. Direct trans-esterification of methyl and ethyl esters with alcohols under basic catalytic conditions occurs in good yield in the presence of Aliquat [34, 35]. 

Various combinations of reactant(s) and process conditions are potentially available to synthesize polyesters [Fakirov, 2002 Goodman, 1988], Polyesters can be produced by direct esterification of a diacid with a diol (Eq. 2-120) or self-condensation of a hydroxy carboxylic acid (Eq. 2-119). Since polyesterification, like many step polymerizations, is an equilibrium reaction, water must be continuously removed to achieve high conversions and high molecular weights. Control of the reaction temperature is important to minimize side reactions such as dehydration of the diol to form diethylene glycol... 

Schreiber and co-workers (436) prepared a library calculated to contain 2.18 million polycyclic compounds through the 1,3-dipolar cycloaddition of a number of nitrones with alkenes supported on TentaGel S NH2 resin (Scheme 1.83). (—)-Shikimic acid was converted into the polymer bound epoxycyclohexenol carboxylic acid 376 (or its enantiomer), coupled to the resin via a photolabile linker developed by Geysen and co-workers (437) to allow release of the products from the resin in the presence of live cells by ultraviolet (UV)-irradiation. A range of iodoaromatic nitrones (377) was then reacted with the ot,p-unsaturation of the polymer-bound amide in the presence of an organotin catalyst, using the tandem esterification/ dipolar cycloaddition methodology developed by Tamura et al. (84,85) Simultaneous cyclization by PyBrop-mediated condensation of the acid with the alcohol... 

Kauss (39) has shown that the esterification of the carboxyl groups in the D-galacturonic acid chain takes place by a transfer of the methyl groups from S-adenosyl-L-methionine, analogous to the case in which the 4-methyl ether groups are transferred to D-glucuronic acid of hemi-cellulose (40). 

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