Esterification of carboxylic acids and alcohols

A differently anchored Mukaiyama reagent is the N-methylpyridinium iodide salt 57 [71], which has been obtained by reaction of the Merrifield resin with N-Boc-aminocaproic acid in the presence of cesium carbonate to give the supported ester 55 (Scheme 7.19). Further Boc-deprotection and reaction with 6-chloronicoti-noyl chloride in the presence of Hxinig s base furnished the anchored 2-chloro-pyridine 56, which was transformed into the final N-methylpyridinium salt 57 after N-methylation in neat methyl iodide. This supported reagent has been used in the rapid microwave-assisted esterification of carboxylic acids and alcohols in the presence of triethylamine as base, with dichloromethane as solvent at 80 °C, the products being obtained in high purity after simple resin filtration [72],... 

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). 

Hf(0Tf)4 was also reported to possess unique reactivity characteristics relative to other Lewis acids. Recent reports indicated that it is capable to catalyze hydrolysis reactions even in the presence of excess water [41]. An example is its capacity to catalyze the efficient direct macrolactonization of secondary acids in high yields (Equation (8.20)). Water was the sole by-product of this reaction. In addition to synthesis of macrolactones and benzolactones this catalyst allowed intermolecular direct esterifications of carboxylic acids and alcohols. 

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 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). 

Taft based his steric effect constants on the assumption that rates of esterification of carboxylic acids with alcohols and of acid catalyzed hydrolysis of carboxylate... 

The Lewis or Bnynstedt acid-catalyzed esterification of carboxylic acids with alcohols to give esters is a typical reaction in which the products and reactants are in equilibrium. 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

Esterification of carboxylic acids with alcohols, including bulky secondary ones, by equimolar di-2-thienyl carbonate (2-DTC) in the presence of a catalytic amount of 4-(dimethylamino)pyridine in toluene solvent at room temperature followed by addition of a catalytic amount of hafnium(IV) trifluoromethanesulfonate, Hf(OTf)4, afforded the corresponding esters in good to high yields. In step 1 (Scheme 1), interaction of the acid and 2-DTC (1) produces the thienyl ester (2) with evolution of CO2 and formation of 2(5H)-thiophenone (3). In step 2, the added Hf(OTf)4 forms with (2) an activated complex (4), alcoholysis of which yields the ester (5) and a further molecule of 2(5H)-thiophenone.1 The procedure was also effective for converting [Pg.48]

Table V summarizes several reactions that have been demonstrated on a laboratory scale 1 know of no industrialized chemical process using Nafion as a superacid catalyst. Although many of the reactions were carried out with stirring a mixture of reactants and Nafion-H, several alkylation, disproportionation, rearrangement, and esterification reactions were performed by means of the flow-reaction method in the liquid or gas phase. For instance, in the esterification of carboxylic acids with alcohols, when a mixture of the acid and alcohol was allowed to flow over a Nafion-H catalyst at 95-125°C with a contact time 5 s, high yields, usually S90%, of the corresponding ester were obtained (82). It had been found that no reactivation of the catalyst was needed because the catalytic activity of the Nafion remained unchanged for prolonged periods of operation.

Esterification.1 This reagent in combination with a catalytic amount of 4-dimethylaminopyridine (DMAP) is very effective for esterification of carboxylic acids with alcohols or thiols at room temperatures. However, reaction of aromatic and hindered acids requires several days at room temperature. French chemists report that only this method is useful for esterification of the protected baccatin III derivative (2) with (2R,3S)-N-benzoyl-0-(l-ethoxyethyl)-3-phenylisoserine (3) to provide the protected taxol derivative (4). A reaction conducted at 73° for 100 hours with 6 equiv. of 1 and 2 equiv. of DMAP produced 4 in 80% yield. Natural taxol, a cancer chemotherapeutic agent, is obtained by removal of the protective groups at C2 and C7 of 4. 

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. 

A titanium triflate, TiCl(OTf)3, proved to be an excellent catalyst for equimolar esterification of a carboxylic acid and an alcohol in the presence of (Me2SiO)4 as a dehydrating agent (Eq. 215) [510]. The catalyst is required only in very small amounts (0.1 mol %) and a variety of combinations of carboxylic acids and alcohols enter this esterification. 

The Mitsunobu esterification of carboxylic acids with alcohols in the presence of Ph3P and DEAD (diethyl azodicarboxylate) occurs under neutral conditions and provides the corresponding esters in high yields. 

Direct room temperature esterification of carboxylic acids with alcohols, including tert. alcohols with the help of dicyclohexylcarbodiimide (DCC) and 4-diakylaminopyridine catalysts 3. 

Esterification. Heating a mixture of carboxylic acids and alcohols with NaHS04.H,0 results in ester formation. 

To obtain rate equations for the esterification reactions (1) and (2), a detailed knowledge of the underlying mechanisms is necessary. For the acid-catalyzed esterification of carboxylic acids with alcohols, the mechanism was proposed (Figure 5.2). 

Esterification. The reaction of carboxylic acids and alcohols in the presence of 1.2 eq. of this pyridinium salt and 2.4 eq. of tri-n-butylamine affords esters... 

Esters are a wide class of organic compounds with the general formnla RCOOR and pro-dnced by esterification of carboxylic acids with alcohols. 

This procedure offers a convenient method for the esterification of carboxylic acids with alcohols and thiols under mild conditions. Its success depends on the high efficiency of 4-d1alkyl aminopyridines as nucleophilic catalysts in group transfer reactions. The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacldic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols. Including polyols,a-hydroxycarboxyl 1c acid esters, and even very acid labile... 

Microwave irradiation has been widely used in organic synthesis on a laboratory scale during the last few years. Several categories of reactions, for example, Diels-Alder reactions, ortAo-Claisen condensations, ene-reactions, oxidations, esterification of carboxylic acids with alcohols, and hydrolysis of esters and amides to carboxylic acids, have been successfully carried out in conventional microwave ovens. Table 26.4, adapted from Majetich and Hicks (1994), provides representative examples of some of these reactions. It can be seen that the conditions under which the conventional and microwave reactions are carried out differ significantly for most reactions. Hence, in comparing reactions with micro-waves with conventional syntheses with reflux, it is necassary to make the comparisons based on the total amount of energy input to the reaction volume. 

Other recent relevant developments have been the replacement of conventional acid catalysts with greener analogues. Direct esterification of carbo Q lic acids and alcohols continues to be a focus of attention. As examples, diphenylammonium triflate 8 and bulky diatylammonium sulfonates were shown to catalyse ester condensation of carboxylic acids and alcohols efficiently, and without the need for azeotropic water removal in the former case. Pentafluorophenylammonium triflate 9 was shown to be an efficient and cost-effective catalyst not only for esterification, but also for thioesterification, transesterification and macrolactone formation without requiring a dehydrating system. The superior catal)4ic efficiency of 9 relative to 8 was ascribed to the lower basicity of the pentafluoroaniline counter amine compared to diphenylamine. In related work, polyaniline... 

The Ti +.mont also acted as a reusable heterogeneous acid catalyst for esterification of carboxylic acids vdth alcohols [101], deprotection of acetals [102], and the condensation of glycerol with ketones or aldehydes into cycHc acetals under mild reaction conditions [103]. 

The development of these molecular descriptors have been based on the physical model of transition states in acid-catalyzed esterification reaction of carboxylic acids and alcohols and acid hydrolysis of esters - standard reactions used by Taft for the development of Eg s empirical steric parameter in the frame of LFER (linear free energy relationship). The physical meaning of the (8, G) shape descriptors is depicted in Fig. 15.3. 

Fig. 15.3 Physical significance of (5,G) parameters for the transition states in reactions (a) acid-catalyzed hydrolysis of esters and esterification of carboxylic acids with alcohols XCOOH + ROH (b) nucleophilic bimolecular substitution, 8 2...

Chakraborti, A.K., Singh, B., Chankeshwara, S.V., Patel, A.R. 2009. Protic acid immobilized on solid support as an extremely efficient recyclable catalyst system for a direct and atom economical esterification of carboxylic acids with alcohols. Journal of Organic Chemistry 74 5967-5974. 

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