Nucleophilic substitution process mechanisms

Table S.16 presents data on some representative nucleophilic substitution processes. The first entry illustrates the use of 1-butyl-l-r/p-bromobenzenesulfonate to dononstrate at primary systems react with inversion, even under solvolysis conditkms in formic acid. The observation of inversion indicates a concerted mechanism in fids weakly nucleophilic solvent.

Much study has been devoted to the mechanisms of these reactions, but firm conclusions are still lacking, in part because the mechanisms vary depending on the metal, the R group, the catalyst, if any, and the reaction conditions. Two basic pathways can be envisioned a nucleophilic substitution process (which might be S l or Sn2) and a free-radical mechanism. This could be an SET pathway, or some other route that provides radicals. In either case, the two radicals R- and R would be in a solvent cage ... 

The refers to a nucleophilic substitution process where some nucleophile attacks an electrophile and substitutes for some part of the electrophile. The E refers to an elimination process where the nucleophile attacks an electrophile and causes the elimination of something. The 1 and 2 refer to the order of the reaction. A 1 (first order) means only one molecule determines the rate of the reaction, whereas a 2 (second order) means that a combination of two molecules determines the rate of the reaction. In many cases, two or more of these mechanisms are competing and more than one product may result. 

On the contrary, in the case of 1-iodonorbomane (a tertiary hahde), the result of the reaction with trimethylstannyl reagents (Me3SnM, M = Li, Na), both in the absence and in the presence of trapping agents, confirmed that the nucleophilic substitution process is governed by competition between polar and radical mechanisms. ... 

There are two general nucleophilic substitution reaction mechanisms (1) a one step process in which the nucleophile enters at the same time the leaving group exits (SN2) and (2) a two step process in which the leaving group departs and then the nucleophile enters (SN1). 

Although steric effects and substituent effects leading to carbonium ion stabilization are of greatest importance in governing the mechanism and relative rate of nucleophilic substitution processes, there are other substituent effects that are recognized and of importance. We have mentioned earlier in this chapter that arylmethyl and allylic cations are stabilized by electron delocalization. It is therefore easy to understand why substitution reactions of the ionization type proceed more rapidly in such systems than in simple alkyl systems. It has also been observed that nucleophilic substitutions of the direct displacement type also take place more readily, but the reason for this is not apparent. Allyl chloride is 33 times more reactive than ethyl chloride toward iodide ion in acetone, and benzyl chloride is 93... 

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. 

Experimental evidence for this pathway is diverse. For example, the reactions occur with a 2 1 stoichiometry, but the rate law is second order (proportional to [M ] and [RX]). Products are generated with racemization at carbon, and the relative reactivity of alkyl halides follows the trend tertiary > secondary > primary > Me. These relative reactivities parallel the stabilities of R instead of the reactivity as an electrophile in a nucleophilic substitution process. Furthermore the alkyl radical intermediate in this mechanism has been trapped, has undergone rearrangements, and has been detected directly by EPR. 

Since ion pairs are undoubtedly important species, the question has arisen as to whether they might be intermediates in all nucleophilic substitution processes. R. A. Sneen and H. M. Robbins suggested that ion pairs might not only be involved in SnI and borderline processes but also in displacements exhibiting the stereochemical and kinetic characteristics of the Sn2 process. They suggested the scheme shown below, in which SOH is a hydroxylic solvent and Nu" is a nucleophilic anion. In this mechanism, reactions with Sn2 characteristics are postulated to occur by nucleophilic attack on the intimate ion pair. 

The migration of methyl to sulphur observed in reactions of o-mercapto-benzoic acid methyl ester with primary aliphatic amines, possibly via an S i mechanism, contributes another example to an extensive list of interactions of aromatic or/Ao-substituents. More conventional nucleophilic substitution processes include syntheses of L-selenomethionine, MeSeCH2 -CHa CH(NH2) C02H, and its c-ethyl and S e-benzyl analogues by treatment of O-toIuene-p-sulphonyl-L-homoserine with appropriate organo-selenium nucleophiles also, analogous reactions of hydroxy-acid... 

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the same as those of alkyl halides Inversion of configuration is observed m 8 2 reac tions of alkyl sulfonates and predominant inversion accompanied by racemization m 8 1 processes... 

Substitution nucleophilic unimolecular(SNl) mechanism (Sec tions 4 9 and 8 8) Mechanism for nucleophilic substitution charactenzed by a two step process The first step is rate determining and is the ionization of an alkyl halide to a carbocation and a halide ion... 

The ionization mechanism for nucleophilic substitution proceeds by rate-determining heterolytic dissociation of the reactant to a tricoordinate carbocation (also sometimes referred to as a carbonium ion or carbenium ion f and the leaving group. This dissociation is followed by rapid combination of the highly electrophilic carbocation with a Lewis base (nucleophile) present in the medium. A two-dimensional potential energy diagram representing this process for a neutral reactant and anionic nucleophile is shown in Fig. 

To make this more specific. Table 5-3 gives examples of several reaction types that fit the RIP pattern. Consider nucleophilic substitution on saturated carbon. The concerted mechanism is the one-step bimolecular 5, 2 process ... 

The mechanism of the nucleophilic substitution of a-halogenosulphoxides depends on structural factors and the nature of a nucleophile and may occur according to two competitive mechanisms a direct 8 2 substitution and an elimination-addition process . Thus, chloromethyl and bromomethyl sulphoxides react with alkoxide and mercaptide anions via an 8, 2 mechanism to give the corresponding a-alkoxy and a-alkylthiomethyl sulphoxides 502, respectively (equation 305). Optically active a-alkoxymethyl and a-alkylthiomethyl sulphoxides can also be obtained in this way - . 

The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 4 of Part A. That mechanistic understanding has contributed to the development of nucleophilic substitution reactions as important synthetic processes. Owing to its stereospecificity and avoidance of carbocation intermediates, the Sw2 mechanism is advantageous from a synthetic point of view. In this section we discuss... 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

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