Addition, nucleophilic tetrahedral mechanism

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... 

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 ... 

The electrophile shown in step 2 is the proton. In almost all the reactions considered in this chapter the electrophilic attacking atom is either hydrogen or carbon. It may be noted that step 1 is exactly the same as step 1 of the tetrahedral mechanism of nucleophilic substitution at a carbonyl carbon (p. 331), and it might be expected that substitution would compete with addition. However, this is seldom the case. When A and B are H, R, or Ar, the substrate is an aldehyde or ketone and these almost never undergo substitution, owing to the extremely poor nature of H, R, and Ar as leaving groups. For carboxylic acids and their... 

Kinetic studies of the nucleophilic reactions of azolides have demonstrated that the aminolyses and alcoholyses proceed via a bimolecular addition-elimination reaction mechanism, as does the neutral hydrolysis of azolides of aromatic carboxylic acids. Aliphatic carboxylic acid azolides which are subject to steric hindrance can be hydrolyzed in aqueous medium by an 5n1 process. There have been many studies of these reactions, and evidence supporting both 5n1 and 5n2 processes leaves the impression that there are features of individual olysis reactions which favour either an initial ionization or a bimolecular process involving a tetrahedral intermediate (80AHC(27)241, B-76MI40701). 

First, we will discuss reactions in which hydrogen or a metallic ion (or in one case phosphorus or sulfur) adds to the heteroatom and second reactions in which carbon adds to the heteroatom. Within each group, the reactions are classified by the nature of the nucleophile. Additions to isocyanides, which are different in character, follow. Acyl substitution reactions that proceed by the tetrahedral mechanism, which mostly involve derivatives of carboxylic acids, are treated at the end. 

Carbonyl compounds react via the tetrahedral mechanism. In this case, on the addition of the nucleophile, the negative charge is borne by the oxygen atom, which is an inherently more stable intermediate than the carbanion version. The tetrahedral intermediate may be isolated when a suitable substrate is used. An example is the formation of the cyanohydrin on the addition of a cyanide ion, which we studied in the chapter on addition reactions to a carbon/ oxygen system. 

Nucleophilic substitution of compounds containing carbon/oxygen double bonds, i.e. carbonyl compounds, proceed via the tetrahedral mechanism. The tetrahedral intermediate may be isolated when a suitable substrate is used, e g. the addition of HCN to a carbonyl compound yields a cyanohydrin. If one of the groups attached to the carbonyl carbon is eliminated, then an overall substitution occurs, e g. in the hydrolysis of an acid chloride. 

AdN-E Tetrahedral mechanism of nucleophilic addition followed by elimination. 

Because transition states may have lifetimes of only several nanoseconds, in most cases, it is impossible to observe them directly. However, there are numerous lines of evidence for the existence of a tetrahedral-like transition state for non-enzymatic ester hydrolysis a) substitution at a carbonyl group (as is the case of the hydrolysis of esters) most often proceeds by a tetrahedral mechanism, a second-order addition-elimination (for a review of this mechanism, see (23)) b) the kinetics are pseudo-first order either in the substrate or in the nucleophile, as predicted by the mechanism c) for the 180 labeled esters, the 180 isotope is detectable in both products (in a "normal" Sjj2 reaction all the 180 isotopes should remain in the acid functionality)(24) d) in a few cases tetrahedral intermediates have been isolated or detected spectrally (25). 

For less acidic alcohols, nucleophilic participation is ineffective because of the low tendency for such alcohols to function as leaving groups. The tetrahedral intermediate formed by intramolecular addition simply returns to starting material because the carboxylate is a much better leaving roup than the alkoxide. In contrast to aspirin itself, acetyl salicylates with electron-withdrawing groups (o- and p-nitro analogs) hydrolyze via the nucleophilic catalysis mechanism. ... 

The key step in a basealdol reaction is nucleophilic addition of the enolate anion from one carbonyl-containing molecule to the carbonyl group of another carbonyl-containing molecule to form a tetrahedral carbonyl addition intermediate. This mechanism is illustrated by the aldol reaction between two molecules of acetaldehyde. Notice that OH is a true catalyst An OH is used in Step 1, but another OH is generated in Step 3. Notice also the parallel between Step 2 of the aldol reaction and the reaction of Grignard reagents with aldehydes and ketones (Section 12.5) and the first step of their reaction with esters (Section 14.7). Each type of reaction involves the addition of a carbon nucleophile to the carbonyl carbon of another molecule. 

As has been shown by Bender s elegant experiments [85] using the isotope labelling technique, the reaction of nucleophilic substitution at the carbonyl carbon proceeds not as a concerted one-step transfer of the acyl group, but rather as a two-step associative process by the addition-elimination (AdE) mechanism Bac2 with the formation of the tetrahedral intermediate XXVII ... 

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. 

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 ... 

In the first stage of the hydrolysis mechanism, water undergoes nucleophilic addition to the carbonyl group to for rn a tetrahedral inter mediate. This stage of the process is analogous to the hydration of aldehydes and ketones discussed in Section 17.6. 

When written in this way it is clear what is happening. The mechanisms of these reactions are probably similar, despite the different p values. The distinction is that in Reaction 10 the substituent X is on the substrate, its usual location but in Reaction 15 the substituent changes have been made on the reagent. Thus, electron-withdrawing substituents on the benzoyl chloride render the carbonyl carbon more positive and more susceptible to nucleophilic attack, whereas electron-donating substituents on the aniline increase the electron density on nitrogen, also facilitating nucleophilic attack. The mechanism may be an addition-elimination via a tetrahedral intermediate ... 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

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