And the tetrahedral mechanism

The mechanism for the lipase-catalyzed reaction of an acid derivative with a nucleophile (alcohol, amine, or thiol) is known as a serine hydrolase mechanism (Scheme 7.2). The active site of the enzyme is constituted by a catalytic triad (serine, aspartic, and histidine residues). The serine residue accepts the acyl group of the ester, leading to an acyl-enzyme activated intermediate. This acyl-enzyme intermediate reacts with the nucleophile, an amine or ammonia in this case, to yield the final amide product and leading to the free biocatalyst, which can enter again into the catalytic cycle. A histidine residue, activated by an aspartate side chain, is responsible for the proton transference necessary for the catalysis. Another important factor is that the oxyanion hole, formed by different residues, is able to stabilize the negatively charged oxygen present in both the transition state and the tetrahedral intermediate. 

Several studies have been made of the directionality of approach by the nucleophile. ° Menger ° has proposed for reactions in general, and specifically for those hat proceed by the tetrahedral mechanism, that there is no single definable preferred transition state, but rather a cone of trajectories. All approaches within this cone lead to reaction at comparable rates it is only when the approach comes outside of the cone that the rate falls. 

Nucleophilic substitution at a vinylic carbon is difficult (see p. 433), but many examples are known. The most common mechanisms are the tetrahedral mechanism and the closely related addition-elimination mechanism. Both of these mechanisms are impossible at a saturated substrate. The addition-elimination mechanism has... 

Of course, we have seen (p. 430) that SnI reactions at vinylic substrates can be accelerated by a substituents that stabilize that cation, and that reactions by the tetrahedral mechanism can be accelerated by P substituents that stabilize the carbanion. Also, reactions at vinylic substrates can in certain cases proceed by addition-elimination or elimination-addition sequences (pp. 428, 430). 

Table 10.6 is an approximate listing of groups in order of SnI and Sn2 reactivity. Table 10.7 shows the main reactions that proceed by the Sn2 mechanism (if R = primary or, often, secondary alkyl) Table 10.8 shows the main reactions that proceed by the tetrahedral mechanism. 

Not all the reactions in this chapter are actually nucleophilic substitutions. In some cases the mechanisms are not known with enough certainty even to decide whether a nucleophile, an electrophile, or a free radical is attacking. In other cases (such as 10-79), conversion of one compound to another can occur by two or even all three of these possibilities, depending on the reagent and the reaction conditions. However, one or more of the nucleophilic mechanisms previously discussed do hold for the overwhelming majority of the reactions in this chapter. For the alkylations, the Sn2 is by far the most common mechanism, as long as R is primary or secondary alkyl. For the acylations, the tetrahedral mechanism is the most common. 

Ion 21 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone the mechanism is similar to the tetrahedral mechanism of Chapter 10, but with the charges reversed. If it combines with chloride, the product is a 3-halo ketone, which can be isolated, so that the result is addition to the double bond (see 15-45). On the other hand, the p-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition-elimination mechanism. In the case of unsymmetrical alkenes, the attacking ion prefers the position at which there are more hydrogens, following Markovnikov s rule (p. 984). Anhydrides and carboxylic acids (the latter with a proton acid such as anhydrous HF, H2SO4, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts double-bond migrations are occasionally encountered so that, for example, when 1 -methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene. ... 

The first step is usually, but not always, rate determining. It can be seen that this mechanism greatly resembles the tetrahedral mechanism discussed in Chapter 10 and, in another way, the arenium ion mechanism of electrophilic aromatic substitution. In all three cases, the attacking species forms a bond with the... 

Reactivity factors in additions to carbon-hetero multiple bonds are similar to those for the tetrahedral mechanism of nucleophilic substitution. If A and/or B are electron-donating groups, rates are decreased. Electron-attracting substituents increase rates. This means that aldehydes are more reactive than ketones. Aryl groups are somewhat deactivating compared to alkyl, because of resonance that stabilizes the substrate molecule but is lost on going to the intermediate ... 

Many such examples are known. In most cases where the stereochemistry has been investigated, retention of configuration is observed,225 but stereoconvergence (the same product mixture from an E or Z substrate) has also been observed,226 especially where the carbanionic carbon bears two electron-withdrawing groups. It is not immediately apparent why the tetrahedral mechanism should lead to retention, but this behavior has been ascribed, on the basis of molecular orbital calculations, to hyperconjugation involving the carbanionic electron pair and the substituents on the adjacent carbon.227... 

For substrates that react by the tetrahedral mechanism, electron-withdrawing groups increase the rate and electron-donating groups decrease it. 

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