Tetrahedral intennediate

Step 3 The oxonium ion fonned in step 2 loses a proton to give the tetrahedral intennediate in its neutral fonn. This step concludes the first stage in the mechanism. 

More than one fonn of the tetrahedral intennediate can be present at a paiticulai pH, and the most abundant fonn need not be the one that gives most of the product. A less abundant fonn may react at a faster rate than a more abundant one. 

First stage Fonnation of the tetrahedral intennediate by nucleophilic addition of water to the carbonyl group... 

The 5/) -hybridized carbon of an acyl chloride is less sterically hindered than the sp -hybridized carbon of an alkyl chloride, making an acyl chloride more open toward nucleophilic attack. Also, unlike the Sn2 transition state or a carbocation intennediate in an SnI reaction, the tetrahedral intennediate in nucleophilic acyl substitution has a stable anangement of bonds and can be fonned via a lower energy transition state. 

Step 3 Deprotonation of the oxoniuin ion to give the neutral form of the tetrahedral intennediate... 

Step 4 Protonation of the tetrahedral intennediate at its alkoxy oxygen... 

Step 5 Dissociation of the protonated fonn of the tetrahedral intennediate to an alcohol and the protonated fonn of the car boxylic acid... 

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 in step 2. Loss of a proton from the resulting oxoniurn ion gives the neutral fonn of the tetrahedral intennediate in step 3 and completes the first stage of the mechanism. 

Once formed, the tetrahedral intennediate can revert to starting materials by merely reversing the reactions that formed it, or it can continue onward to products. In the second 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 oxoniurn ion, which loses a molecule of alcohol in step 5. Along with the alcohol, the protonated form of the carboxylic acid arises by dissociation of the tetrahedral intermediate. Its deprotonation in step 6 completes the process. 

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 intennediate. 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 desciibed in the preceding section. Bender showed that basic ester hydrolysis was not conceited and, like acid hydrolysis, took place by way of a tetrahedral intennediate. The nature of the experiment was the sane, and the results were similai to those observed in the acid-catalyzed reaction. Ethyl benzoate emiched in 0 at the caibonyl oxygen was subjected to hydrolysis in base, and samples were isolated before saponification was complete. The recovered ethyl benzoate was found to have lost a portion of its isotopic label, consistent with the fonnation of a tetrahedral intennediate ... 

All these facts—the obseiwation of second-order kinetics, nucleophilic attack at the carbonyl group, and the involvement of a tetrahedral intennediate—are accommodated by the reaction mechanism shown in Figure 20.5. Like the acid-catalyzed mechanism, it has two distinct stages, nanely, fonnation of the tetrahedral intennediate 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, ineversible, and this makes the overall reaction rneversible. 

Steps 2 and 4 are proton-transfer reactions and are very fast. Nucleophilic addition to the carbonyl group has a higher activation energy than dissociation of the tetrahedral intennediate step 1 is rate-detennining. 

The reaction of anmonia and amines with esters follows the sane general mechanistic course as other nucleophilic acyl substitution reactions (Figure 20.6). A tetrahedral intennediate is fonned in the first stage of the process and dissociates in the second stage. 

In base the tetrahedral intennediate is fonned in a manner analogous to that proposed for ester saponification. Steps 1 and 2 in Figure 20.8 show the fonnation of the tetrahedral intennediate in the basic hydrolysis of amides. In step 3 the basic amino group of the tetrahedral intennediate abstracts a proton from water, and in step 4 the derived ammonium ion dissociates. Conversion of the carboxylic acid to its conesponding carboxylate anion in step 5 completes the process and renders the overall reaction ineversible. 

Step 2 Nucleophilic addition of the ester enolate to the caibonyl group of the neutral ester. The product is the anionic fonn of the tetrahedral intennediate. 

The only difference between che aldol condeitsation td an aldehyde or ketone end the Claieen condensation of an ester involves the fate of the tnt> tially formed tetrahedral intennediate. The tetrahedral intermediate in tite aldo reaction is protonalcd to give an alcohol product exactly the behav> ior previously seen for aldehydes and ketones (Sectuwi 194>. The telrahe dra) intermediate in the Claisen reaction expels an alkoxide leaving group to yield an acyl substitution product exactly the behavior proviously seen for esters (Section 21.6)i. 

The tetrahedral intennediate has three potential leaving groups on carbon two hydroxyl groups and a chlorine. In the second stage of the reaction, the tetrahedral intermediate dissociates. Loss of chloride from the tetrahedral intermediate is faster than loss of hydroxide chloride is less basic than hydroxide and is a better leaving group. The tetrahedral intermediate dissociates because this dissociation restores the resonance-stabilized carbonyl group. 

Fig. 10. The diastereoisomeric tetrahedral intennediates in the thiolysis of l- and D-guests by (5H57). (a) (SH57) L-guest (more stable) (b) (S)-(57) D-guest (less stable).

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