Carboxylic acids esterification mechanism

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]. 

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 19 14 The mechanism of acid catalyzed esterification involves some key fea tures that are fundamental to the chemistry of carboxylic acids and then-derivatives... 

A similar mechanism has been proposed for the esterification of carboxylic acids ... 

Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid. 

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. 

Before we turn to "mechanisms" let us repeat how a catalyst works. We can reflux carboxylic acids and alcohols and nothing happens until we add traces of mineral acid that catalyse esterification. We can store ethene in cylinders for ages (until the cylinders have rusted away) without the formation of polyethylene, although the formation of the latter is exothermic by more than 80 kjoule/mol. We can heat methanol and carbon monoxide at 250 °C and 600 bar without acetic acid being formed. After we have added the catalyst the desired products are obtained at a high rate. 

Mechanism of esterification of carboxylic acids The esterification of carboxylic acids with alcohols is a kind of nncleophilic acyl snbstitntion. Protonation of the carbonyl ojq gen activates the carbonyl gronp towards nncleophilic addition of the alcohol. Proton transfer in the tetrahedral intermediate converts the hydrojq l group into - 0H2 group, which, being a better leaving group, is eliminated as neutml water molecule. The protonated ester so formed finally loses a proton to give the ester. 

The hydrolysis of an ester to alcohol and acid (1) and the esterification of a carboxylic acid with an alcohol (2) are shown here as an example of the Sn2 mechanism. Both reactions are made easier by the marked polarity of the C=0 double bond. In the form of ester hydrolysis shown here, a proton is removed from a water molecule by the catalytic effect of the base B. The resulting strongly nucleophilic OH ion attacks the positively charged carbonyl C of the ester (la), and an unstable sp -hybridized transition state is produced. From this, either water is eliminated (2b) and the ester re-forms, or the alcohol ROH is eliminated (1b) and the free acid results. In esterification (2), the same steps take place in reverse. 

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. 

Catalysis by Solid Acids. Two aspects are considered here. The first aspect is concerned with transesterification reactions catalyzed by solid acids. Unfortunately, little research dealing with this subject has been reported in the literature. The second aspect deals with esterification reactions of carboxylic acids (or FFAs). This second part addresses an important characteristic of inexpensive TG feedstocks, i.e., high FFA content. Ideally, an active solid catalyst should be able to carry out transesterification and esterification simultaneously, thus eliminating pretreatment steps. It is likely that heterogeneous catalysts that perform well in esterification should also be good candidates for transesterification since the mechanisms for both reactions are quite similar. 

Reactivity of Functional Groups. The reactivity of the functional groups of liquid prepolymers significantly affects the processing, cure behavior, and the ultimate mechanical properties of the cured binder and propellant. The reactivity of carboxyl groups of CTPB can be determined by the rate of reaction with n-butyl alcohol. The rate of esterification is measured from the rate of water evolution from the alcohol—carboxylic acid reaction, and a plot of water evolved vs. time then permits the calculation of the corresponding rate constants. 

EtjN,663 and N,N -carbonyldiimidazole (100).664 In the latter case easily alcoholyzed im-idazolides (101) are intermediates. BF3 promotes the esterification by converting the acid to RCO+ BF3OH, so the reaction proceeds by an AacI type of mechanism. The use of BF etherate is simple and gives high yields.665 Carboxylic esters can also be prepared by treating carboxylic acids with /-butyl ethers and acid catalysts.666... 

This is formally the reverse of the BA1,1 cleavage of an ester, and is the only one-stage mechanism for ester formation available for the ionized carboxyl group. Numerous methods are, of course, available which involve initial electrophilic attack on the carboxylate group, followed by a displacement at the carbonyl carbon atom of the intermediate formed, which is often an anhydride. An example134 is the esterification of carboxylic acids in the presence ofp-toluenesulphonyl chloride in pyridine, viz-... 

Kinetic Considerations. Extensive kinetie and mechanistic studies have been made on the esterification of carboxylic acids since Berthclot and Saint-Gilles first studied the esterification of acetic acid. A number of mechanisms for acid- and base-catalyzed esterification have been proposed. One possible mechanism for the bimolecular acid-catalyzed ester hydrolysis and esterification is shown below. 

Another practical limitation of esterification reactions is steric hindrance. If either the acid or the alcohol participants possesses highly branched groups, the positions of equilibrium are less favorable and the rates of esterification are slow. In general, the ease of esterification for alcohols, ROH, by the mechanism described is primary R > secondary R > tertiary R with a given carboxylic acid. 

Exercise 15-9 An alternative and plausible mechanism for esterification of carboxylic acids is shown by the following steps ... 

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... 

Write the steps in the mechanism for the acid-catalyzed (Fischer) esterification of a given carboxylic acid with a given alcohol. 

Fig. H. Mechanism for the acid-catalysed esterification of a carboxylic acid.

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 Aac2 mechanism (Figure 6.22) of ester hydrolysis represents an SN reaction at the carboxyl carbon, which follows the general mechanism of Figure 6.5. Acid-catalyzed hydrolyses of carboxyhc esters that are derived from primary or from secondary alcohols take place according to the Aac2 mechanism. The reverse reactions of these hydrolyses follow the same mechanism, namely, the acid-catalyzed esterifications of carboxylic acids with alcohols. In the esterifications, the same intermediates are formed as during hydrolysis, but in the opposite order. 

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