Tetrahedral intermediates in reactions

Until a few years ago there was only indirect evidence for the existence of the species postulated as tetrahedral intermediates in reactions of derivatives of carboxylic acids (cf. Kirby, 1972). Now, however, it is possible to generate some of them in solution at sufficiently high concentrations for their uv and nmr spectra to be measured and for their reactions to be studied. It is the purpose of this review to record progress that has been made in this area. 

Is there stereoelectronic control in the formation and cleavage of tetrahedral intermediates (in reactions with participation of heterocycles) 02ACR28. 

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 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. 

Using HSCoA and HS—ACP as abbreviations for coenzyme A and acyl carrier protein, respectively, write a structural formula for the tetrahedral intermediate in the preceding reaction. j... 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The intermediates 74 and 76 can now lose OR to give the acid (not shown in the equations given), or they can lose OH to regenerate the carboxylic ester. If 74 goes back to ester, the ester will still be labeled, but if 76 reverts to ester, the 0 will be lost. A test of the two possible mechanisms is to stop the reaction before completion and to analyze the recovered ester for 0. This is just what was done by Bender, who found that in alkaline hydrolysis of methyl, ethyl, and isopropyl benzoates, the esters had lost 0. A similar experiment carried out for acid-Catalyzed hydrolysis of ethyl benzoate showed that here too the ester lost However, alkaline hydrolysis of substimted benzyl benzoates showed no loss. This result does not necessarily mean that no tetrahedral intermediate is involved in this case. If 74 and 76 do not revert to ester, but go entirely to acid, no loss will be found even with a tetrahedral intermediate. In the case of benzyl benzoates this may very well be happening, because formation of the acid relieves steric strain. Another possibility is that 74 loses OR before it can become protonated to 75. Even the experiments that do show loss do not prove the existence of the tetrahedral intermediate, since it is possible that is lost by some independent process not leading to ester hydrolysis. To deal with this possibility. Bender and Heck measured the rate of loss in the hydrolysis of ethyl trifluorothioloacetate- 0 ... 

Nucleophilic substitution at RSO2X is similar to attack at RCOX. Many of the reactions are essentially the same, though sulfonyl halides are less reactive than halides of carboxylic acids. The mechanisms are not identical, because a tetrahedral intermediate in this case (148) would have five groups on the central atom. Though this is possible (since sulfur can accommodate up to 12 electrons in its valence shell) it seems more likely that these mechanisms more closely resemble the Sn2 mechanism, with a trigonal bipyramidal transition state (148). There are two major experimental results leading to this conclusion. 

However, micelles do not always favor reactions of higher order. In dilute OH-, reaction of activated amides, for example (18), is typically second order in OH-, but the order decreases to one with increasing [OH-] because the tetrahedral intermediate is converted rapidly into products (Menger and Donohue, 1973 Cipiciani et al., 1979). These reactions are speeded by cationic micelles, but in the micelles they are always first order in OH-, even when the total concentration of OH- is low. This is simply because the micelles concentrate OH-, so that the tetrahedral intermediate in (18) is... 

The mechanisms of aminolysis of substituted phenyl quinoline-8- and -6-carboxylates, (36) and (37), have been evaluated using AMI semiempirical and HF/6-31- -G(d) ab initio quanmm mechanical methods to study the ammonolyses of the model systems vinyl c/x-3-(methyleneamino)acrylate (38), c/x-2-hydroxyvinyl di-3-(methyleneamino)acrylate (39) and vinyl rranx-3-(methyleneamino)acrylate (40). Both experimental and computational results support the formation of a tetrahedral intermediate in the reaction. The results of this study are fully consistent with the experimental observations for the aminolyses of variously substituted phenyl quinoline-8- (36) and -6-carboxylates (37). ... 

All of this evidence supports the existence of tetrahedral intermediates in a-chymotrypsin-catalysed reactions, but it should be noted that O-exchange with water is not observed in deacylation of cinnamoyl- 0-chymotrypsin, in contrast with the hydrolysis of O-cinnamoyl-N-acetylserinamide where such exchange is detected (Bender and Heck, 1967). Lack of exchange in the enzyme reaction could reflect interactions of the tetrahedral intermediate with the protein. 

Further indirect evidence for the incursion of tetrahedral intermediates in acyl-transfer reactions has been obtained from experiments which indicate a change in rate-determining step and hence the incursion of an intermediate (Jencks and Gilchrist, 1964, 1968 Jencks, 1969 Johnson, 1967 Schowen et al., 1966 Fedor and Bruice, 1965 Hibbert and Satchell, 1967 Chaturvedi et... 

Both the experimental and calculated equilibrium constants indicate the great thermodynamic instability of hemiorthoesters with respect to the corresponding esters and show why it is normally impossible to detect the tetrahedral intermediates in acyl-transfer reactions. On going from intermolecular to intramolecular reactions the tetrahedral intermediate becomes relatively more stable, and if the structure is more rigid (cf. [120], [121] in Table 17) or more sterically crowded (cf. [119]) the tetrahedral intermediate is more stable still. However, it is only with structues as rigid as tetrodotoxin or with the trifluoroacetate of pinacol that the hemiorthoester is more stable than the ester (see Section 1). ... 

The tetrahedral intermediate in the chymotrypsin reaction pathway, and the second tetrahedral intermediate that forms later, are sometimes referred to as transition states, which can lead to confusion. An intermediate is any chemical species with a finite lifetime, finite being defined as longer than the time required for a molecular vibration ( 10-13 seconds). A transition state is simply the maximum-energy species formed on the reaction coordinate and does not have a finite lifetime. The tetrahedral intermediates formed in the chy-motrypsin reaction closely resemble, both energetically and structurally, the transition states leading to their formation and breakdown. However, the intermediate represents a committed stage of completed... 

The, s/j2-hybridized carbon of an acyl chloride is less sterically hindered than the sp3-hybridized carbon of an alkyl chloride, making an acyl chloride more open toward nucleophilic attack. Also, unlike the SN2 transition state or a carbocation intermediate in an SN1 reaction, the tetrahedral intermediate in nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state. 

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

Figure 3-1. The formation of a tetrahedral intermediate in the reaction of a nucleophile with a carbonyl compound.

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