Hydrolysis of esters by acids

A catalyst is defined as a substance that influences the rate or the direction of a chemical reaction without being consumed. Homogeneous catalytic processes are where the catalyst is dissolved in a liquid reaction medium. The varieties of chemical species that may act as homogeneous catalysts include anions, cations, neutral species, enzymes, and association complexes. In acid-base catalysis, one step in the reaction mechanism consists of a proton transfer between the catalyst and the substrate. The protonated reactant species or intermediate further reacts with either another species in the solution or by a decomposition process. Table 1-1 shows typical reactions of an acid-base catalysis. An example of an acid-base catalysis in solution is hydrolysis of esters by acids. 

The most numerous cases of homogeneous catalysis are by certain ions or metal coordination compounds in aqueous solution and in biochemistry, where enzymes function catalytically. Many ionic effects are known. The hydronium ion H3O and the hydroxyl ion OH catalyze hydrolyses such as those of esters ferrous ion catalyzes the decomposition of hydrogen peroxide decomposition of nitramide is catalyzed by acetate ion. Other instances are inversion of sucrose by HCl, halogenation of acetone by H and OH , hydration of isobutene by acids, hydrolysis of esters by acids, and others. 

The catalyst is the same phase as the reactants and products. Examples are hydrolysis of esters by acids (liquid-liquid), oxidation of SOi by NO (vapor-vapor), and decomposition of potassium chlorate by MnOi (solid-solid). Usually, the liquid phase is most common, with both catalyst and reactants in solution. 

Esters react by both acid and nucleophile initiated mechanisms. Hydrolysis of esters by acid catalysis is exactly the reverse of the mechanism for the acid-catalyzed esterification of a carboxylic acid. Base-catalyzed hydrolysis of esters is called saponification. Hydroxide attacks to form a tetrahedral intermediate. Loss of alkoxide ion then occurs. The alkoxide neutralizes the resulting carboxylic acid to form the salt. 

Acidic Hydrolysis. Hydrolysis of esters by use of water and a mineral acid leads to an equiUbrium mixture of ester, alcohol, and free carboxyHc acid. Complete reaction can only be achieved by removal of alcohol or acid from the equiUbrium. Because esters have poor solubiUty in water, the reaction rate in dilute acids is fairly low. Therefore, emulsifiers such as sulfonated oleic acid or sulfonated aromatic compounds (TwitcheU reagent) are added to facihtate the reaction. 

The hydrolysis of esters by the nickel derivative (271) provided an early example of the use of a metal-capped cyclodextrin as a catalyst (shown here as its p-nitrophenyl acetate inclusion complex) (Breslow Overman, 1970 Breslow, 1971). The synthesis of this host involves the following steps (i) covalent binding of the pyridine dicarboxylic acid moiety to cyclodextrin, (ii) coordination of Ni(n) to this species, and (iii)... 

Now let us see how the imidazole grouping of histidine can be involved in the general acid-catalysed and general base-catalysed hydrolysis of esters by enzymes. In essence, the chemical and enzymic reactions are very similar. This is to be... 

From the previous examples it is apparent that simple imprinting with a transition state analogue does not lead to cavities with sufficient catalytic activity in addition, catalytically active groups have to be placed in proper position within the cavity. This is also true for catalytic antibodies since it was shown that for, example, a guanidinium group (of the amino acid L-arginine) plays an important role in the catalysis of the basic hydrolysis of esters by a catalytic antibody. 

One of the most typical reactions of esters is the saponification or hydrolysis of esters by strong bases such as NaOH or KOH. Boiling ester with a water solution of KOH or NaOH yields the salt of a carboxylic acid and the corresponding alcohol. 

Hydrolytic stability - Hydrolysis of esters to giye acids and alcohols is a facile reaction and can proceed at elevated temperatures in the presence of water. Hydrolysis of ester generates acid that can be very corrosive to metal components and can catalyze the base stock decomposition process. Therefore, hydrolytic stability of esters is an important issue. Much work has been carried out to improve the hydrolytic stability by varying the composition of acids and alcohols. Generally, esters made from aromatic acids or from more sterically hindered acids, such as 2-alkyl substituted acids or neo-acids, have improved hydrolytic stabilities. Proper branching of the acids protect the carbonyl ester function from the detrimental attack of water. The presence of impurity, such as trace acid or metal, can catalyze the decomposition and hydrolysis of ester. Compared to PAO or alkylaromatic base stocks, ester hydrolysis is always an issue of concern in many lubrication applications. 

Experimental evidence to prove this postulate come from four sources. A study of the oxidation of acetals by ozone, acid hydrolysis of cyclic orthoesters, concurrent carbonyl-oxygen exchange and hydrolysis of esters by using oxygen-18 labeling, and basic hydrolysis of N,N-dialkylated imidate salts. We will briefly examine results from the last three approaches. Then we will try to apply this concept to the hydrolysis of ester and amide substrates by serine proteases. 

The most common situation studied is that of a film reacting with some species in solution in the substrate, such as in the case of the hydrolysis of ester monolayers and of the oxidation of an unsaturated long-chain acid by aqueous permanganate. As a result of the reaction, the film species may be altered to the extent that its area per molecule is different or may be fragmented so that the products are soluble. One may thus follow the change in area at constant film pressure or the change in film pressure at constant area (much as with homogeneous gas reactions) in either case concomitant measurements may be made of the surface potential. 

There are a few documented examples of studies of ligand effects on hydrolysis reactions. Angelici et al." investigated the effect of a number of multidentate ligands on the copper(II) ion-catalysed hydrolysis of coordinated amino acid esters. The equilibrium constant for binding of the ester and the rate constant for the hydrolysis of the resulting complex both decrease in the presence of ligands. Similar conclusions have been reached by Hay and Morris, who studied the effect of ethylenediamine... 

Inspired by the many hydrolytically-active metallo enzymes encountered in nature, extensive studies have been performed on so-called metallo micelles. These investigations usually focus on mixed micelles of a common surfactant together with a special chelating surfactant that exhibits a high affinity for transition-metal ions. These aggregates can have remarkable catalytic effects on the hydrolysis of activated carboxylic acid esters, phosphate esters and amides. In these reactions the exact role of the metal ion is not clear and may vary from one system to another. However, there are strong indications that the major function of the metal ion is the coordination of hydroxide anion in the Stem region of the micelle where it is in the proximity of the micelle-bound substrate. The first report of catalysis of a hydrolysis reaction by me tall omi cell es stems from 1978. In the years that... 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

In this reaction, three steps, ie, acylation, cyclization, and replacement of the chlorine atom by the hydroxyl group, take place simultaneously in concentrated sulfuric acid. In the course of cyclization 2,7-dichlorofluoran (31) may be formed as a by-product presumably through the carbonium ion (30) ihustrated as follows. The addition of boric acid suppresses this pathway and promotes the regular cyclization to form the anthraquinone stmcture. The stable boric acid ester formed also enables the complete replacement of chlorine atoms by the hydroxyl group. Hydrolysis of the boric acid ester of quinizarin is carried out by heating in dilute sulfuric acid. The purity of quinizarin thus obtained is around 90%. Highly pure product can be obtained by sublimation. 

Optically Active Acids and Esters. Enantioselective hydrolysis of esters of simple alcohols is a common method for the production of pure enantiomers of esters or the corresponding acids. Several representative examples are summarized ia Table 4. Lipases, esterases, and proteases accept a wide variety of esters and convert them to the corresponding acids, often ia a highly enantioselective manner. For example, the hydrolysis of (R)-methyl hydratropate [34083-55-1] (40) catalyzed by Hpase P from Amano results ia the corresponding acid ia 50% yield and 95% ee (56). Various substituents on the a-carbon (41—44) are readily tolerated by both Upases and proteases without reduction ia selectivity (57—60). The enantioselectivity of many Upases is not significantly affected by changes ia the alcohol component. As a result, activated esters may be used as a means of enhancing the reaction rate. 

Hydrolysis. Esters are cleaved (hydroly2ed) into an acid and an alcohol through the action of water. This hydrolysis is cataly2ed by acids or bases. The mechanistic aspects of ester hydrolysis have received considerable attention and have been reviewed (16). For most esters only two reaction pathways are important. Both mechanisms involve a tetrahedral intermediate and addition-elimination reactions i7i7... 

Pyridazinecarboxylic acids can also be prepared by hydrolysis of esters, nitriles and amides in the presence of acids or alkali. Another interesting method is partial decarboxylation of... 

Hydrolysis of esters is speeded up by both acids and bases. Soluble aflcylaiyl sulfonic acids or sulfonated ion exchange resins are suitable. 

Digestion (Section 29.1) The first stage of catabolism, in which food is broken down by hydrolysis of ester, glycoside (acetal), and peptide (amide) bonds to yield fatty acids, simple sugars, and amino acids. 

Taft, following Ingold," assumed that for the hydrolysis of carboxylic esters, steric, and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base (see the discussion of ester-hydrolysis mechanisms. Reaction 10-10). Rate differences would therefore be caused only by the field effects of R and R in RCOOR. This is presumably a good system to use for this purpose because the transition state for acid-catalyzed hydrolysis (7) has a greater positive charge (and is hence destabilized by —I and stabilized by +1 substituents) than the starting ester. 

---