Nucleophilic substitution direct displacement mechanism

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

You have seen that nucleophilic acyl substitution reactions take place by a mechanism in which a tetrahedral intermediate is formed and subsequently collapses. The tetrahedral intermediate, however, is too unstable to be isolated. How, then, do we know that it is formed How do we know that the reaction doesn t take place by a one-step direct-displacement mechanism (similar to the mechanism of an Sn2 reaction) in which the incoming nucleophile attacks the carbonyl carbon and displaces the leaving group—a mechanism that would not form a tetrahedral intermediate ... 

The limiting cases of nucleophilic substitution have been described as the ionization mechanism (SnI, substitution-nucleophilic-unimolecular) and the direct displacement mechanism (8 2, substitution-nucleophilic-bimolecular Gleave et al., 1935). The S l and Sn2 mechanisms describe the extremes in nucleophilic substitution reactions. Pure SnI and Sn2 reaction mechanisms, however, are rarely observed. More often a mix of these reaction mechanisms are occurring simultaneously. 

Trifluoromethanesulfonate (triflate) is an exceptionally good leaving group, enabling nucleophilic substitution reactions to be carried out on normally unreactive substrates. Acetolysis of cyclopropyl triflate, for example, occurs 10 times faster than acetolysis of cyclopropyl tosylate. Similar rate enhancements are seen in systems in which the direct displacement mechanism is operative, as summarized in Table 5.7. 

Many other types of organic compounds can be conveniently prepared by nucleophilic substitution processes. These are exemplified in Scheme 5.4. It should be noted that the processes most used for synthetic transformations involve substrates that are reactive in the direct-displacement mechanism, i.e., primary and unhindered secondary alkyl halides and sulfonates. The tendency toward elimination in tertiary alkyl systems is sufficiently pronounced to limit the usefulness of nucleophilic substitution reactions in synthetic transformations involving these systems. 

Aromatic nucleophilic substitution by superoxide occurs by a mechanism different from that encountered in aliphatic nucleophilic substitution reactions of this ion. Thus, reaction of enriched potassium superoxide with l-bromo-2,4-dinitro-benzene catalyzed by dicyclohexyl-18-crown-6 in benzene saturated with unlabeled oxygen results in 2,4-dinitrophenol almost devoid of label. The loss of label in this reaction rules out a direct displacement mechanism. This result is consistent with electron transfer from superoxide anion to the arene to form an intermediate aromatic anion radical which reacts with oxygen (from all sources) to yield phenol. This mechanism is formulated in equation 8.12. Examples of this reaction are presented in Table 8.7. 

In each of the mechanisms, the transition slates are very reactive. Therefore, the first step is rale-controlling and the di.s.sociative process is called unimolecular nucleophilic substitution SN). The associative and direct displacement mechanisms, which require two partners in the transition stale, are called bimolecular nucleophilic substitutions SN2-... 

Fig. S.2. Potential eneigy diagram for nucleophilic substitution by the direct displacement (S 2) mechanism.

The points that we have emphasized in this brief overview of the S l and 8 2 mechanisms are kinetics and stereochemistry. These features of a reaction provide important evidence for ascertaining whether a particular nucleophilic substitution follows an ionization or a direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the Sj l mechanism and those exhibiting second-order kinetics react by the 8 2 mechanism. Many nucleophilic substitutions are carried out under conditions in which the nucleophile is present in large excess. When this is the case, the concentration of the nucleophile is essentially constant during die reaction and the observed kinetics become pseudo-first-order. This is true, for example, when the solvent is the nucleophile (solvolysis). In this case, the kinetics of the reaction provide no evidence as to whether the 8 1 or 8 2 mechanism operates. 

Nucleophilic substitution is the widely accepted reaction route for the photosubstitution of aromatic nitro compounds. There are three possible mechanisms11,12, namely (i) direct displacement (S/v2Ar ) (equation 9), (ii) electron transfer from the nucleophile to the excited aromatic substrate (SR wlAr ) (equation 10) and (iii) electron transfer from the excited aromatic compound to an appropriate electron acceptor, followed by attack of the nucleophile on the resultant aromatic radical cation (SRi w 1 Ar ) (equation 11). Substituent effects are important criteria for probing the reaction mechanisms. While the SR wlAr mechanism, which requires no substituent activation, is insensitive to substituent effects, both the S/v2Ar and the Sr+n lAr mechanisms show strong and opposite substituent effects. 

---