Hydroxide-Ion-Promoted Ester Hydrolysis

The rate of hydrolysis of an ester can be increased by hydroxide ion. Like an acid catalyst, hydroxide ion increases the rates of the two slow steps of the reaction—namely, formation of the tetrahedral intermediate and collapse of the tetrahedral intermediate. 

The two potential leaving groups in the tetrahedral intermediate (H0 and CH30 ) have the same leaving propensity. Elimination of HO re-forms the ester, whereas elimination of CH30 forms a carboxylic acid 

The final products are not the carboxylic acid and methoxide ion because if only one base is protonated, it will be the stronger base. Therefore, the final products are the carboxylate ion and methanol because CH30 is more basic than RCOO.  

In addition, a smaller fraction of the negatively charged tetrahedral intermediate becomes protonated in a basic solution. (Recall that the relative amounts of the neutral and negatively charged tetrahedral intermediates depend on the pH of the solution and the pK value of the neutral tetrahedral intermediate see Section 2.10.) 

Because carboxylate ions are negatively charged, they do not react with nucleophiles. Therefore, the hydroxide-ion-promoted hydrolysis of an ester, unlike the acid-catalyzed hydrolysis of an ester, is not a reversible reaction. 

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Early chemists could envision several possible mechanisms for hydroxide-ion-promoted ester hydrolysis ... 

To answer this question, Myron Bender investigated the hydroxide-ion-promoted hydrolysis of ethyl benzoate, with the carbonyl oxygen of ethyl benzoate labeled with 0. When he isolated ethyl benzoate from an incomplete reaction mixture, he found that some of the ester was no longer labeled. If the reaction had taken place by a one-step direct-displacement mechanism, all the isolated ester would have remained labeled because the carbonyl group would not have participated in the reaction. On the other hand, if the mechanism involved a tetrahedral intermediate, some of the isolated ester would no longer be labeled because some of the label would have been transferred to the hydroxide ion. By this experiment. Bender provided evidence for the reversible formation of a tetrahedral intermediate. 

D. N. Kursanov, a Russian chemist, proved that the bond that is broken in the hydroxide-ion-promoted hydrolysis of an ester is the acyl C — O bond, rather than the alkyl C — O bond, by studying the reaction of the following ester with H0 /H20 ... 

The intermediate shown here is formed during the hydroxide-ion-promoted hydrolysis of the ester group. Propose a mechanism for the reaction. 

The hydrolysis of an ester in the presence of hydroxide ion is called a hydroxide-ion-promoted reaction rather than a base-catalyzed reaction because hydroxide ion increases the rate of the first step of the reaction by being a better nucleophile than water— not by being a stronger base than water—and because hydroxide ion is consumed in the overall reaction. To be a catalyst, a species must not be changed by or consumed in the reaction. Therefore, hydroxide ion is actually a reagent rather than a catalyst, so it is more accurate to call the reaction a hydroxide-ion-promoted reaction than a hydroxide-ion-catalyzed reaction. 

Strong bases also promote ester hydrolysis through an addition-elimination mechanism (Sections 19-7 and 20-1). The base (B) converts the poor nucleophile water into the negatively charged and more highly nucleophilic hydroxide ion. 

Ester hydrolysis can also be promoted by nucleophilic catalysis. If a component of the reaction system is a more effective nucleophile toward the carbonyl group than hydroxide ion or water under a given set of conditions, an acyl-transfer reaction can take place to form an intermediate ... 

It has been known for many years that the rate of hydrolysis of a-amino acid esters is enhanced by a variety of metal ions such as copper(II), nickel(II), magnesium(H), manganese(II), cobalt(II) and zinc(II).338 Early studies showed that glycine ester hydrolysis can be promoted by a tridentate copper(II) complex coupled by coordination of the amino group and hydrolysis by external hydroxide ion (Scheme 88).339 Also, bis(salicylaldehyde)copper(II) promotes terminal hydrolysis of the tripeptide glycylglycylglycine (equation 73).340 In this case the iV-terminal dipeptide fragment... 

Initially studies of metal ion-promoted hydrolysis were centred on simple monoamin esters.36,44,43 However, many of the initial investigations led to rather conflicting results. Th reactions are difficult to study due to the low formation constants of the active complexes. Mor recent measurements46 48 have provided rate constants (Table 4) which show only order c magnitude agreement however, it has been possible to establish that hydroxide ion is th predominant nucleophile at pH values of ca. 5. Higher pH values lead to precipitation of meti hydroxides. Evidence for nucleophilic attack by water has also been obtained.46"48... 

Somewhat similar effects are seen in the copper(II)-promoted hydrolysis of O-acetyl-2-pyridinecarboxaldoxime (47) (equation 20).215 In this case, water attack and hydroxide ion attack are accelerated by 1.1x10 and 2.2 xlO7 times respectively. Detailed analysis indicates that Cuu-bound water or hydroxide reacts with the carbonyl carbon of the ester as shown in (48). Promotion includes contributions from increases in the effective nucleophile concentration in addition to an enhancement in the leaving group ability. General base catalysis in the attack of coordinated water is also observed. 

Hendry P, Sargeson AM. Metal ion promoted phosphate ester 43. hydrolysis. Intramolecular attack of coordinated hydroxide ion. 

Fife, T.H., and T.J, Przystas. 1985. Divalent metal ion catalysis in the hydrolysis of esters of picolinic acid. Metal ion promoted hydroxide ion and water catalyzed reactions. J. Am. Chem. Soc. 107 1041-1047. 

Differential Solvation of Reactants and Transition States. It should always be kept in mind that solvent effects can modify the energy of both the reactants and the transition state. It is the difference in the solvation that is the basis for changes in activation energies and reaction rates. Thus, although it is common to discuss solvent effects solely in terms of reactant solvation or transition state solvation, this is an oversimplification. A case that illustrates this point is the base-promoted hydrolysis of esters by hydroxide ion. 

Lanthanide hydroxide gels have been known for about 50 years to catalyze the hydrolysis of polyphosphates and phosphate esters (20). However, the study of these systems is fraught with similar difficulties to those mentioned previously, that is, the inability to be able to identify the complexes responsible for the activation. Butcher and Westheimer (20) in 1955 investigated the hydrolysis of a variety of phosphate esters by La(OH)3 gels. The gel promotes the hydrolysis of the esters by up to 10 -fold. The reaction is at the P-center as shown by tracer studies. In that communication, the mechanism by which the metal ion promotes hydrolysis could not be specified although a mechanism involving the intermediacy of the metaphosphate anion was suggested as a possibility. 

The hydrolysis of 2-(l,10-phenanthrolyl)phosphate not unexpectedly shows a catalytic effect for a variety of metal ions (59). The metal ions Cu, NP", Co, and Zn " have some effect on the rate of its hydrolysis, but only Cu has a large effect. The ester binds all four metal ions very well, with saturation kinetics observed above 1 mM for all the metal ions involved. The Cu ion was most effective at promoting hydrolysis of the ester. The rate enhancement is not great, however, amounting to 300-fold at pH 8 and 85 °C. The reaction was proposed to proceed via attack of H2O on complex 6 or its kinetic equivalent, for example, attack of hydroxide ion on the protonated form of complex 6. Apparently, the Cu " coordinated OH ion, when formed as expected at pH 7, is sterically restrained from attack at the P center. 

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