Characteristics of the Sn2 Reaction

Now that we know how Sn2 reactions occur, we need to see how they can be used and what variables affect them. Some Sn2 reactions are fast, and some are slow some take place in high yield and others in low yield. Understanding the factors involved can be of tremendous value. Let s begin by recalling a few things about reaction rates in general. 

The first Sn2 reaction variable to look at is the stmcture of the substrate. Because the Sn2 transition state involves partial bond formation between the incoming nucleophile and the alkyl halide carbon atom, it seems reasonable that a hindered, bulky substrate should prevent easy approach of the nucleophile, making bond formation difficult. In other words, the transition state for reaction of 

Vinylic halides (R2C=CRX) and aryl halides are not shown on this reactivity list because they are unreactive toward Sn2 displacement. This lack of reactivity is due to steric factors the incoming nucleophile would have to approach in 

Another variable that has a major effect on the Sn2 reaction is the nature of the nucleophile. Any species, either neutral or negatively charged, can act as a nucleophile as long as it has an unshared pair of electrons that is, as long as it is a Lewis base. If the nucleophile is negatively charged, the product is neutral if the nucleophile is neutral, the product is positively charged. 

A wide array of substances can be prepared using nucleophilic substitution reactions. In fact, we ve already seen examples in previous chapters. The reaction of an acetylide anion with an alkyl halide discussed in Section 9.8, for instance, is an 5 2 reaction in which the acetylide nucleophile displaces a halide leaving group. 

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Comparison of the calculated nucleophilic accelerations of 9, 17, and 106 to the degree of inversion (72, 74, and 87%, respectively) for Vla-c shows that even though the kinetic effects of solvent assistance are significant, this fact does not lead to the complete inversion characteristic of the SN2 reaction as found in acetolysis of 2-octyl tosylate (45). The best description of the first intermediate in the solvolysis of Vla-c would thus appear to be the solvated ion pair shown in Scheme II. In this species, the solvent is involved in nucleophilic solvation of the central carbon as well as the remainder of the carbocation and also participates in electrophilic solvation of the anion. Numerous solvent molecules are involved, and no strong interaction of a single nucleophilic solvent molecule at the central carbon leading to exclusive inversion occurs. 

The reaction of Pd complexes (such as Pd(PhsP)4) with organic halides and related compounds has been used to prepare a number of stable Pd alkyl and vinyl compounds. This reaction with alkyl halides has the characteristics of an Sn2 reaction. Primary halides react faster than secondary halides. Also, when a chiral halide is used, such as (X)-(-F)-benzyl-o -D chloride, the benzyl palladium product is formed with inversion of configuration at the benzylic carbon (equation 8). With vinylic halides, retention of configuration at the double bond is observed... 

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 success of the present method depends critically on the initial presence of an alcohol to trap the intermediate phosphonium species.12 If the alcohol is added last, the R3P—CX4 reaction described above (an exothermic process for the more nucleophilic phosphines) may go to completion, in which case little or no alkyl halide is formed.13 Since the reaction displays several characteristics of an SN2 process, it is thought to proceed by the pathway illustrated ... 

Facile SN2 substitution reactions of halogens are expected from the electron-attracting characteristics of the neighboring carbonyl function, which should make the transition state for attack by a nucleophilic reagent more favorable ... 

The origin of intrinsic barriers to reactions of carbocations has been discussed by Richard.8 He suggests that reaction of water with a carbocation possessing a strongly localized positive charge such as CH3+ will not only be favorable thermodynamically but possess a very low intrinsic barrier. By contrast, a high intrinsic barrier is associated characteristically with an SN2 reaction, in which... 

Chemical reactivity is influenced by solvation in different ways. As noted before, the solvent modulates the intrinsic characteristics of the reactants, which are related to polarization of its charge distribution. In addition, the interaction between solute and solvent molecules gives rise to a differential stabilization of reactants, products and transition states. The interaction of solvent molecules can affect both the equilibrium and kinetics of a chemical reaction, especially when there are large differences in the polarities of the reactants, transition state, or products. Classical examples that illustrate this solvent effect are the SN2 reaction, in which water molecules induce large changes in the kinetic and thermodynamic characteristics of the reaction, and the nucleophilic attack of an R-CT group on a carbonyl centre, which is very exothermic and occurs without an activation barrier in the gas phase but is clearly endothermic with a notable activation barrier in aqueous solution [76-79]. 

We commented earlier in this chapter that carboxylic acids are similar in some respects to both alcohols and ketones. Like alcohols, carboxylic acids can be deprotonated to give anions, which are good nucleophiles in Sn2 reao tions. Like ketones, carboxylic acids undergo attack by nucleophiles on the carbonyl group. In addition, carboxylic acids undergo other reactions characteristic neither of alcohols nor ketones. Figure 20.4 shows some of the general reactions of carboxylic acids. 

The overall effect of the reaction results in the addition of R-X to the metal. Substrate types that will undergo this mode of OA are generally limited to R = benzyl, allyl, and methyl. Some acyl compounds [R(C=0)-X] also readily undergo OA. These are the same substrates that are most reactive in SN2 displacements or in nucleophilic acyl substitution. Other characteristics of these OA reactions associated with the SN2 pathway include the following ... 

The nucleophilicity of sulfur and its ability to stabilize a-carbanions provide sulfur compounds with unique opportunities for sigmatropic processes consecutive rearrangements are no exception. The formation of salt (140) via Sn2 alkylation of ( )-2-butenyl bromide (139) followed by deprotonation leads to the intermediate allyl vinyl ether (141) which, under the conditions of the deprotonation, undergoes a thio-Claisen rearrangement to afford thioamide (143 Scheme 10). Thermolysis of (143) at elevated temperature affords the Cope product (142) in addition to some of its deconjugated isomer. Several unique characteristics of the thio-Claisen sequence should be noted first, the heteroatom-allyl bond is made in the alkylation step, this connection teing not notrtudly practised in the parent Claisen reaction ... 

The characteristics of Sn2 and SnI reactions are summarized in Table 10.5. Remember that the 2 in Sn2 and the 1 in SnI refer to the molecularity— how many molecules are involved in the rate-determining step. Thus, the rate-determining step of an Sn2 reaction is bimolecular, whereas the rate-determining step of an SnI reaction is... 

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