Tetrahedral intermediate hydrolysis

Fig. 1. The rate-determining step in the neutral hydrolysis of paramethoxy-phenyl dichloroacetate. In the reactant state (a) a water molecule is in proximity of the carbonyl carbon after concerted proton transfer to a second water molecule and electron redistribution, a tetrahedral intermediate (b) is formed.

In the first stage of the hydrolysis mechanism water undergoes nucleophilic addi tion to the carbonyl group to form a tetrahedral intermediate This stage of the process IS analogous to the hydration of aldehydes and ketones discussed m Section 17 6... 

FIGURE 20 2 Hydrolysis of an acyl chloride proceeds by way of a tetrahedral intermediate For mationofthe tetrahedral intermediate is rate determining... 

FIGURE 20 4 The mecha nism of acid catalyzed ester hydrolysis Steps 1 through 3 show the formation of the tetrahedral intermediate Dissociation of the tetrahe dral intermediate is shown in steps 4 through 6... 

Once formed the tetrahedral intermediate can revert to starting materials by merely reversing the reactions that formed it or it can continue onward to products In the sec ond stage of ester hydrolysis the tetrahedral intermediate dissociates to an alcohol and a carboxylic acid In step 4 of Figure 20 4 protonation of the tetrahedral intermediate at Its alkoxy oxygen gives a new oxonium ion which loses a molecule of alcohol m step 5 Along with the alcohol the protonated form of the carboxylic acid arises by dissocia tion of the tetrahedral intermediate Its deprotonation m step 6 completes the process... 

The most important species m the mechanism for ester hydrolysis is the tetrahe dral intermediate Evidence m support of the existence of the tetrahedral intermediate... 

Once It was established that hydroxide ion attacks the carbonyl group in basic ester hydrolysis the next question to be addressed concerned whether the reaction is concerted or involves a tetrahedral intermediate In a concerted reaction the bond to the leaving group breaks at the same time that hydroxide ion attacks the carbonyl... 

In an extension of the work described m the preceding section Bender showed that basic ester hydrolysis was not concerted and like acid hydrolysis took place by way of a tetrahedral intermediate The nature of the experiment was the same and the results were similar to those observed m the acid catalyzed reaction Ethyl benzoate enriched m 0 at the carbonyl oxygen was subjected to hydrolysis m base and samples were isolated before saponification was complete The recovered ethyl benzoate was found to have lost a por tion of Its isotopic label consistent with the formation of a tetrahedral intermediate... 

Mechanistically amide hydrolysis is similar to the hydrolysis of other carboxylic acid derivatives The mechanism of the hydrolysis m acid is presented m Figure 20 7 It proceeds m two stages a tetrahedral intermediate is formed m the first stage and disso ciates m the second... 

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

Section 2010 Ester hydrolysis can be catalyzed by acids and its mechanism (Figure 20 4) is the reverse of the mechanism for Fischer esterification The reaction proceeds via a tetrahedral intermediate... 

Section 20 11 Ester hydrolysis m basic solution is called saponification and proceeds through the same tetrahedral intermediate (Figure 20 5) as m acid catalyzed hydrolysis Unlike acid catalyzed hydrolysis saponification is irreversible because the carboxylic acid is deprotonated under the reac tion conditions... 

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... 

Hydrolysis reactions involving tetrahedral intermediates are subject to steric and electronic effects. Electron-withdrawing substituents faciUtate, but electron-donating and bulky substituents retard basic hydrolysis. Steric effects in acid-cataly2ed hydrolysis are similar to those in base-cataly2ed hydrolysis, but electronic effects are much less important in acid-cataly2ed reactions. Higher temperatures also accelerate the reaction. 

Three-dimensional potential energy diagrams of the type discussed in connection with the variable E2 transition state theory for elimination reactions can be used to consider structural effects on the reactivity of carbonyl compounds and the tetrahedral intermediates involved in carbonyl-group reactions. Many of these reactions involve the formation or breaking of two separate bonds. This is the case in the first stage of acetal hydrolysis, which involves both a proton transfer and breaking of a C—O bond. The overall reaction might take place in several ways. There are two mechanistic extremes ... 

The hydrolysis of simple imines occurs readily in aqueous acid and has been studied in great detail by kinetic methods. The precise mechanism is a fimction of the reactant structure and the pH of the solution. The overall mechanism consists of an addition of water to the C=N bond, followed by expulsion of the amine from a tetrahedral intermediate. ... 

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

Insight into the factors that govern breakdown of tetrahedral intermediates has also been gained by studying the hydrolysis of amide acetals. If the amine is expelled, an ester is formed, whereas elimination of an alcohol gives an amide ... 

Nucleophilic participation is important only for esters of alcohols that have pK <13. Specifically, phenyl and trifluoroethyl esters show nucleophilic catalysis, but methyl and 2-chloroethyl esters do not. This result reflects the fete of the tetrahedral intermediate that results fi om nucleophilic participation. For relatively acidic alcohols, the alkoxide group can be eliminated, leading to hydrolysis via nucleophilic catalysis ... 

The kinetics of the hydrolysis of some imines derived from benzophenone anc primary amines revealed the normal dependence of mechanism on pH with ratedetermining nucleophilic attack at high pH and rate-determining decomposition of the tetrahedral intermediate at low pH. The simple primary amines show a linear correlation between the rate of nucleophilic addition and the basicity of the amine Several diamines which were included in the study, in particular A, B, and C, al showed a positive (more reactive) deviation from the correlation line for the simple amines. Why might these amines be more reactive than predicted on the basis of thei ... 

Assume that the usual mechanism for hydrolysis of an imine, Im, is operative, i.e., that the hydrolysis occurs through a tetrahedral intermediate, TI ... 

FIGURE 20.3 An acid catalyzes the hydrolysis of a carboxylic acid anhydride by increasing the rate of the first stage of the mechanism. The faster the tetrahedral intermediate is formed, the faster the rate of hydrolysis. 

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