Ester Hydrolysis and Exchange

Esters can be hydrolyzed in either basic or acidic solution. In acidic solution, the reaction is reversible. The position of the equilibrium depends on the relative concentration of water and the alcohol. In aqueous solution, hydrolysis occurs. In alcoholic solution, the equilibrium is shifted in favor of the ester. 

In alkaline aqueous solution, ester hydrolysis is essentially irreversible. 

Alkyl benzoate esters give only a small amount of exchange under basic hydrolysis conditions. This means that reversal of the hydroxide addition must be slow relative to the forward breakdown of the tetrahedral intermediate.  

Satchell and R. S. Satchell, in Chemistry of Carboxylic Acid Derivatives, Vol. 2, Part 1, S. 

Addition, Condensation and Substitution Reactions of Carbonyl Compounds 

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Moving to a,/3-unsaturated esters, hydroxide ion and alkoxide ion (hard nucleophiles) react with ethyl acrylate 4.77 by direct attack at the carbonyl group to give ester hydrolysis and exchange, respectively, whereas the /3-dicar-bonyl enolate ion 4.78 (a soft nucleophile) undergoes a Michael reaction. There is no certainty in this latter reaction that the attack of the enolate anion on the carbonyl group is not a more rapid (and reversible) process. 

Acidic Cation-Exchange Resins. Brmnsted acid catalytic activity is responsible for the successful use of acidic cation-exchange resins, which are also soHd acids. Cation-exchange catalysts are used in esterification, acetal synthesis, ester alcoholysis, acetal alcoholysis, alcohol dehydration, ester hydrolysis, and sucrose inversion. The soHd acid type permits simplified procedures when high boiling and viscous compounds are involved because the catalyst can be separated from the products by simple filtration. Unsaturated acids and alcohols that can polymerise in the presence of proton acids can thus be esterified directiy and without polymerisation. 

Cation-exchange resins are used as catalysts in the produdion of MTBE (methyl tertiary-butyl ether, 2-methoxy-2-methylpropane) and various other oxygenates and, lately, also in the dimerization of isobutene [30]. Other commercial applications of the cation-exchange resins indude dehydration of alcohols, alkylation of phenols, condensation readions, alkene hydration, purification of phenol, ester hydrolysis and other reactions [31]. The major producers of ion-exchange resins are Sybron Chemicals Incorporated [32] (Lewatit resins), Dow Chemical Company [33] (DOWEX resins), Purolite [28] (Purolite resins), and Rohm and Haas Company [27] (Amberlyst resins). 

Bender104 found that when ethyl benzoate, labelled with excess, sO in the carbonyl group, is hydrolyzed at 99°C in isotopically normal aqueous 1 M acid, oxygen exchange between the unreacted ester and the solvent takes place, and the enrichment of the remaining ester decreases steadily as hydrolysis proceeds. This is precisely the result expected if hydrolysis involves a full intermediate and the addition elimination mechanism receives further support from the observation that hydrolysis and exchange proceed at similar rates, with a constant ratio, Arhyd/)tex of 5.2 for ethylbenzoate. The reaction can thus be written as... 

Two types of esterification reaction that can be studied with water as solvent are lactone formation, in which the alcohol is part of the same molecule as the acid, and the lsO-exchange reaction of carboxylic acids, which makes it possible to examine A-2 reactions of carboxylic acids under the conditions used for ester hydrolysis. Work in both these fields confirms the similarities between ester hydrolysis and formation. The hydrolysis and formation of y-butyrolactone have already been discussed (p. 109). We deal here with the lsO-exchange reactions of carboxylic acids. 

Roberts and Urey99 were the first to demonstrate the similarities between ester hydrolysis and formation, and the 180-exchange reaction of carboxylic acids. Not only are all three reactions of the first order in carboxylic acid or ester and the hydronium ion, but the rates of all three are closely similar... 

This is the general mechanism for acid catalyzed oxygen isotope exchange of carboxylic acids and esters, esterification, ester hydrolysis, and amide hydrolysis (see Vol. 10). 

Hydroxide and alkoxide ions, both hard nucleophiles, react with ethyl acrylate 93, an a,p-unsaturated ester, by direct attack at the carbonyl carbon to bring about ester hydrolysis and ester exchange, respectively. However, the enolate 94, a soft nucleophile, reacts in conjugate manner to form 95 predominantly. In an alternate pathway, it is also likely that the enolate 94 reacts through the oxy anion (hard nucleophile) directiy at the carbonyl carbon (hard electrophile) to generate the species 96, which rearranges in an oxy anion accelerated [3.3] sigmatropic shift manner, as shown, to form 97 and, thus, the above product 95. However, it is not certain that such a direct attack by the enolate is not more rapid and reversible. 

The partial hydrolysis of 4a with methanolic potassium hydroxide followed by selective carboxylic acid reduction with excess borane and treatment of the resulting monoalcohol with methanesulfonyl chloride affords methyl 4-0-methanesulfonyl-2,3-0-isopropylidene-L-threonate (43). Facile displacement of the mesylate with azide followed by ester hydrolysis and catalytic reduction to an amine provides 4-amino-4-deoxy-2,3-0-isopropylidene-L-threonic acid (44). Mild acidic deprotection and ion-exchange desalting of 44 yields (2i ,3 S)-4-amino-4-deoxy-L-threonic acid (45), which has been utilized for the preparation of anthopleurine 46, the alarm pheromone of the sea anemone Anthopleura elegantissima [4] (Scheme 11). 

In ester synthesis and exchange reactions, as well as in hydrolysis re tions induced by PEG-lipase in hydrophobic media, the existence of a trace amount of water in the reaction system was most important in terms of the reactions proceeding. Matsushima et al. [67] carried out a kinetics study of PEG-lipase in transparent benzene solution to estimate the value of water, one of the substrates of lipase in the ester hydrolytic reaction. Indoxyl acetate was hydrolyzed by PEG-lipase to form acetic acid and 3-hydroxyindole, which was photometrically determined. A double-reciprocal plot of the velocity of the indoxyl acetate hydrolysis against water concentration at a given concentration of indoxyl acetate indicated that the hydrolysis took place as a double-displacement reaction (ping-pong reaction). The apparent Michaelis-Menten constant of water and the maximum velocity were calculated to be = 7 X 10 M and Vmax = 4700 xmol/min/mg of protein, respectively. 

This is the same mechanism as that given above for esters, in equation (42). The difference between esters and amides is apparent from a comparison of the two tetrahedral intermediates [5] and [17], The former contains three oxygens, any of which can be protonated, resulting in much lsO exchange being observed when the reaction takes place in 180-enriched water,275,276 but [17] contains a much more basic nitrogen, which will be protonated preferentially and lead to much less 180 exchange, as observed.274 277,278 Also, ammonium ion formation makes the overall reaction irreversible, unlike ester hydrolysis. The calculated solvent isotope effect for the Scheme 15 process is 1.00,280 exactly in accord with experimental observation.278,279... 

W. J. Irwin, K. A. Belaid, Drug-Delivery by Ion-Exchange. Hydrolysis and Rearrangement of Ester Prodrugs of Propranolol , hit. J. Pharm. 1988, 46, 57-67. 

Cu " -catalysed hydrolysis and 5 4 for alkaline hydrolysis of 0-labelled ester. Formation of the tetrahedral intermediate in the scheme of equation (31) is indicated by the observed 0-exchange. However, interactions of the carbonyl oxygen and the metal ion... 

Esters can be hydrolyzed nonenzymatically in acidic and alkahne solutions. In both cases, a tetrahedral intermediate is indicated on the basis of the measured rates of hydrolysis and the rates of oxygen isotope exchange. 

Solid esters are easily crystallisable materials. It is important to note that esters of alcohols must be recrystallised either from non-hydroxylic solvents (e.g. toluene) or from the alcohol from which the ester is derived. Thus methyl esters should be crystallised from methanol or methanol/toluene, but not from ethanol, n-butanol or other alcohols, in order to avoid alcohol exchange and contamination of the ester with a second ester. Useful solvents for crystallisation are the corresponding alcohols or aqueous alcohols, toluene, toluene/petroleum ether, and chloroform (ethanol-free)/toluene. Carboxylic acid esters derived from phenols are more difficult to hydrolyse and exchange, hence any alcoholic solvent can be used freely. Sulphonic acid esters of phenols are even more resistant to hydrolysis they can safely be crystallised not only from the above solvents but also from acetic acid, aqueous acetic acid or boiling n-butanol. 

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