Tetrahedral mechanism intermediates

Section 19.10 Ester hydrolysis in basic solution is called saponification and proceeds through the same tetrahedral intermediate (Mechanism 19.4) as in acid-catalyzed hydrolysis. Unlike acid-catalyzed hydrolysis, saponification is irreversible because the carboxylic acid is deprotonated under the reaction conditions. 

This mechanism combines features of both the tetrahedral intermediate and acylium ion mechanisms. Like the tetrahedral intermediate mechanism, bond making to the nucleophile contributes to the transition state. Like the ionization mechanism, the bond to the leaving group is partially broken at the transition state. The latter makes it more likely to compete with the tetrahedral intermediate mechanism in reactions of acyl chlorides and less likely in reactions of anhydrides, esters, and amides. 

Toth et al. have thoroughly studied the rearrangement their kinetic determinations suggest a general acid-catalyzed mechanism (Scheme 115) (1578). Some points remain unclear, however why is the intermediate (181) written as a transition state when it is known that a tetrahedral intermediate (181b or 181b ) could as well be postulated How does this... 

The lack of examples demonstrating the reactivity on C-2 may be the misleading impression that this atom is not electrophilic, contrary to what is indicated from charge diagrams. Such is not the case as the Cook s rearrangement demonstrates (209, 212). A logical mechanism for this reaction involves the tetrahedral intermediate (88) (Scheme 42). This... 

A mechanism consistent with these facts is presented m Figure 19 7 The six steps are best viewed as a combination of two distinct stages Formation of a tetrahedral intermediate characterizes the first stage (steps 1-3) and dissociation of this tetra hedral intermediate characterizes the second (steps 4-6)... 

Step 3 The oxonium ion formed m step 2 loses a proton to give the tetrahedral intermediate m its neutral form This step concludes the first stage m the mechanism... 

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... 

Protonation of the carbonyl oxygen as emphasized earlier makes the carbonyl group more susceptible to nucleophilic attack A water molecule adds to the carbonyl group of the protonated ester m step 2 Loss of a proton from the resulting oxonium ion gives the neutral form of the tetrahedral intermediate m step 3 and completes the first stage of the mechanism... 

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... 

All these facts—the observation of second order kinetics nucleophilic attack at the carbonyl group and the involvement of a tetrahedral intermediate—are accommodated by the reaction mechanism shown m Figure 20 5 Like the acid catalyzed mechanism it has two distinct stages namely formation of the tetrahedral intermediate and its subsequent dissociation All the steps are reversible except the last one The equilibrium constant for proton abstraction from the carboxylic acid by hydroxide is so large that step 4 is for all intents and purposes irreversible and this makes the overall reaction irreversible... 

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... 

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... 

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... 

Aldehydes and ketones undergo reversible addition reactions with alcohols. The product of addition of one mole of alcohol to an aldehyde or ketone is referred to as a hemiacetal or hemiketal, respectively. Dehydration followed by addition of a second molecule of alcohol gives an acetal or ketal. This second phase of the process can be catalyzed only by acids, since a necessary step is elimination of hydroxide (as water) from the tetrahedral intermediate. There is no low-energy mechanism for base assistance of this... 

In general terms, there are three possible mechanisms for addition of a nucleophile and a proton to give a tetrahedral intermediate in a carbonyl addition reaction. 

There are examples of each of these mechanisms, and a three-dimensional potential energy diagram can provide a useful general framework within which to consider specific addition reactions. The breakdown of a tetrahedral intermediate involves the same processes but operates in the opposite direction, so the principles that are developed will apply equally well to the reactions of the tetrahedral intermediates. Let us examine the three general mechanistic cases in relation to the energy diagram in Fig. 8.3. 

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. ... 

The nucleophilic catalysis mechanism only operates when the alkoxy group being hydrolyzed is not much more basic than the nucleophilic catalyst. This relationship can be imderstood by considering the tetrahedral intermediate generated by attack of the potential catalyst on the ester ... 

When the leaving group is better, breakdown can occur directly from A. This is the case when R"0 is a phenolate anion. The mechanism also depends upon the pH and the presence of general acids and bases because the position of the equilibria among the tetrahedral intermediates and their rates of breakdown are determined by these factors. 

The usual hydrolysis mechanism in strongly acidic solution involves addition of water to the O-protonated amide, followed by breakdown of the tetrahedral intermediate ... 

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 ... 

Nucleophilic acyl substitutions follow a two-stage mechanism and proceed by way of a tetrahedral intermediate. 

We have seen this theme before in Section 19.14 when we presented the mechanism of the Fischer esterification. As was the case then, formation of the tetrahedral intermediate is rate-determining. 

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. 

FIGURE 20.4 The mechanism of acid-catalyzed ester hydrolysis. Steps 1 through 3 show the formation of the tetrahedral intermediate. Dissociation of the tetrahedral intermediate is shown in steps 4 through 6. 

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