Ester Fonnation

When esterification is the objective, water is removed from the reaction mixture to encourage ester fonnation. When ester hydrolysis is the objective, the reaction is caiiied out in the presence of a generous excess of water. Both reactions illustrate the application of Le Ch elier s principle (Section 6.10) to organic synthesis. 

The mechanism of acid-catalyzed ester hydrolysis is presented in Figure 20.4. It is precisely the reverse of the mechanism given for acid-catalyzed ester fonnation in Section 19.14. Like other nucleophilic acyl substitutions, it proceeds in two stages. A... 

One of the arguments against the existence of micelles in solutions of cellulose derivatives is the fact that when cellulose is converted into its derivative, e.g. an ester, the degree of polymerization remains almost unchanged. This however only occurs when ester fonnation is carried out under strictly controlled conditions (nitration at low temperature with nitric and phosphoric acids mixture — p. 341, or with nitric, acetic acids and acetic anhydride mixtures — p. 344). The relevent data found by Staudinger and Mohr [32] are collected in Table 40. 

Kirby, A.J. (1972) Hydrolysis and formation of esters of organic acids, in Comprehensive Chemical Kinetics. Volume 10 Ester Fonnation and Hydrolysis and Related Reactions, Banford C.H. and Tipper C.F.H. (Eds.), Elsevier, Amsterdam, 57-202. 

No 0-allylation is observed in formation of the six-membered ring compound 79 by intramolecular allylation of the /3-keto ester 78(15,57]. Intramolecular allylation is useful for lactone fonnation. On the other hand, exclusive formation of the eight-membered ring lactone 81 from 80 may be in part derived from the preference for the nucleophile to attack the less substituted terminus of the allyl system[58]. 

In an extension of the work desciibed in the preceding section. Bender showed that basic ester hydrolysis was not conceited and, like acid hydrolysis, took place by way of a tetrahedral intennediate. The nature of the experiment was the sane, and the results were similai to those observed in the acid-catalyzed reaction. Ethyl benzoate emiched in 0 at the caibonyl oxygen was subjected to hydrolysis in base, and samples were isolated before saponification was complete. The recovered ethyl benzoate was found to have lost a portion of its isotopic label, consistent with the fonnation of a tetrahedral intennediate ... 

In base the tetrahedral intennediate is fonned in a manner analogous to that proposed for ester saponification. Steps 1 and 2 in Figure 20.8 show the fonnation of the tetrahedral intennediate in the basic hydrolysis of amides. In step 3 the basic amino group of the tetrahedral intennediate abstracts a proton from water, and in step 4 the derived ammonium ion dissociates. Conversion of the carboxylic acid to its conesponding carboxylate anion in step 5 completes the process and renders the overall reaction ineversible. 

At least two protons must be present at the a carbon for the equilibrium to favor product fonnation. Claisen condensation is possible for esters of the type RCH2CO2R, but not for R2CHCO2R. ... 

Mixed Claisen condensations aie analogous to mixed aldol condensations and involve carbon-caibon bond fonnation between the a-caibon atom of one ester and the carbonyl car bon of another. 

Alternatively, a-bromo-(2-chlorophenyl)acetic acid (15) was prepared by treatment of 2-chlorobenzaldehyde with tribromomethane in dioxane with an aqueous solution of potassium hydroxide, Fonnation of methyl ester 16 was followed by an Sn2 displacement by thieno[3,2-c]pyridine (8) to afford ) an 88% yield of ( )-clopidogrel (2 in two steps. 

Alcohols undergo a large number of reactions. However, these reactions may be grouped into a few general types. Reactions of alcohols may involve the O—H or C—O bonds. Ester formation and salt fonnation are examples of the former class, while conversion to halides is an example of the latter type. 

The kinetics of concerted thermal elimination reactions of a series of ethyl (hetero) arylcarboxylate esters (2-thienyl-, 3-thienyl-, 2-furyl, 3-furyl, 4-pyridyl-, 3-pyridyl-, and 2 -pyridylcarbo x y I ate) in the gas phase seem to indicate that there is tittle charge separation in the transition state (83) this is in contrast with the behaviour of the corresponding /-butyl and isopropyl esters for which a semi-concerted transition state (82) was proposed previously.49 Results of a kinetic study of the gas-phase elimination reactions of methylbenzoyl fonnate (84) and 3-hydroxy-3-methylbutan-2-one (85) have been compared with those for pyruvic acid (87) and benzoylformic acid (86).50 The relative rates of reaction [(86)/(87) 46, (87)/(85) = 1.1 x 105 and (86)/(82) = 1 x 106] reveal that the acidity of the hydrogen atom involved in the elimination process, rather than the initial polarization of the C—C bond which undergoes cleavage, is the important rate-controlling factor. 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh lOAc) -catalyzed reaction with dimethyl diazomalonate but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated carbenoid reactions. Fonnation of a diazomalonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to... 

See Section 362 (Ester-Alkene) for the fonnation of enol esters and Section 367 (Ether-Alkenes) for the fonnation of enol ethers. Many of the methods in Section 60A (Protection of Aldehydes) are also applicable to ketones. 

Considering the formation of a number of simple molecules and free radicals, such as CHj , CH3O, NO, NO2, CO, COj several less defined reactions can take place, for example, the fonnation of nitrite esters [2] ... 

The use of the acid chloride instead of the 2-pyridyl thiol ester also results in fonnation of the 2-ketopyrrole functionality, but significant amounts of the 3-ketopyrrole isomer were also formed. Several rather complex substrates were used as acylating agents in s process with a high degree of success. Some examples of the 2-ketopyrroles that have been prepared are shown in Scheme 12. 

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