Sn2 reaction nucleophiles

WALDEN INVERSION Sn7 AND Sn2 REACTIONS NUCLEOPHILIC SUBSTITUTION REACTIONS WALL EFFECT WASHING ABWARE WASH-OUT WATER... 

Nucleophilicity is a measure of how readily a compound (a nucleophile) is able to attack an electron-deficient atom. Nucleophilicity is measured by a rate constant (k). In the case of an Sn2 reaction, nucleophilicity is a measure of how readily the nucleophile attacks an sp hybridized carbon bonded to a leaving group. 

Figure 6-11 Factors that influence the transition state of the Sn2 reaction nucleophilicity, solvation, steric hindrance, and leaving-group ability.

Relative reactivity is A (nucleophile)/A (methanol) for typical Sn2 reactions and is approximate Data pertain to methanol as the solvent... 

All these reactions of octadecyl p toluenesulfonate have been reported in the chemical literature and all proceed in synthetically useful yield You should begin by identifying the nucleophile in each of the parts to this problem The nucleophile replaces the p toluenesulfonate leaving group in an Sn2 reaction In part (a) the nucleophile is acetate ion and the product of nucleophilic substitution IS octadecyl acetate... 

Primary benzyhc halides are ideal substrates for Sn2 reactions because they are very reactive toward good nucleophiles and cannot undergo competing elimination... 

We will begin with an examination of the reactivity of amines as nucleophiles m Sn2 reactions... 

Nucleophilic attack on oxirane carbon usually proceeds with inversion of configuration (Scheme 44) as expected for Sn2 reactions, even under acid conditions (Scheme 45). Scheme 45 also illustrates the fact that cyclohexene oxides open in a fran5-diaxial manner this is known as the Fiirst-Plattner rule (49HCA275) and there are very few exceptions to it. 

What is the structure of the transition state in an Sn2 reaction In particular-, what is the spatial ariangement of the nucleophile in relation to the leaving group as reactants pass through the transition state on their- way to products ... 

Solvent Effects on the Rate of Substitution by the S/s/2 Mechanism. Polar- solvents are required in typical bimolecular- substitutions because ionic substances, such as the sodium and potassium salts cited earlier in Table 8.1, are not sufficiently soluble in nonpolar-solvents to give a high enough concentration of the nucleophile to allow the reaction to occur at a rapid rate. Other than the requirement that the solvent be polar- enough to dissolve ionic compounds, however, the effect of solvent polarity on the rate of Sn2 reactions is small. What is most imporiant is whether or not the polar- solvent is protic or aprotic. 

Because halides are poorer leaving groups than p-toluenesulfonate, alkyl p-toluene-sulfonates can be converted to alkyl halides by Sn2 reactions involving chloride, bromide, or iodide as the nucleophile. 

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the sfflne as those of alkyl halides. Inversion of configuration is observed in Sn2 reactions of alkyl sulfonates and predominant inversion accompanied by racernization in SnI processes. 

Nucleophilic ring opening of epoxides has many of the features of an Sn2 reaction. Inversion of configuration is observed at the carbon at which substitution occurs. 

Two processes that are consistent with second-order kinetics both involve hydroxide ion as a nucleophile but differ in the site of nucleophilic attack. One of these processes is an Sn2 reaction in which hydroxide displaces caiboxylate from the alkyl group of the ester. 

We consider first the Sn2 type of process. (In some important Sn2 reactions the solvent may function as the nucleophile. We will treat solvent nucleophilicity as a separate topic in Chapter 8.) Basicity toward the proton, that is, the pKa of the conjugate acid of the nucleophile, has been found to be less successful as a model property for reactions at saturated carbon than for nucleophilic acyl transfers, although basicity must have some relationship to nucleophilicity. Bordwell et al. have demonstrated very satisfactory Brjinsted-type plots for nucleophilic displacements at saturated carbon when the basicities and reactivities are measured in polar aprotic solvents like dimethylsulfoxide. The problem of establishing such simple correlations in hydroxylic solvents lies in the varying solvation stabilization within a reaction series in H-bond donor solvents. 

Other measures of nucleophilicity have been proposed. Brauman et al. studied Sn2 reactions in the gas phase and applied Marcus theory to obtain the intrinsic barriers of identity reactions. These quantities were interpreted as intrinsic nucleo-philicities. Streitwieser has shown that the reactivity of anionic nucleophiles toward methyl iodide in dimethylformamide (DMF) is correlated with the overall heat of reaction in the gas phase he concludes that bond strength and electron affinity are the important factors controlling nucleophilicity. The dominant role of the solvent in controlling nucleophilicity was shown by Parker, who found solvent effects on nucleophilic reactivity of many orders of magnitude. For example, most anions are more nucleophilic in DMF than in methanol by factors as large as 10, because they are less effectively shielded by solvation in the aprotic solvent. Liotta et al. have measured rates of substitution by anionic nucleophiles in acetonitrile solution containing a crown ether, which forms an inclusion complex with the cation (K ) of the nucleophile. These rates correlate with gas phase rates of the same nucleophiles, which, in this crown ether-acetonitrile system, are considered to be naked anions. The solvation of anionic nucleophiles is treated in Section 8.3. 

The remarkable enhancement of anion nucleophilicity in Sn2 reactions carried out in dipolar aprotic solvents is a solvation effect.Solvents like DMF and DMSO are very polar owing to the charge separation indicated in 1 and 2. 

Sn2 reactions with anionic nucleophiles fall into this class, and observations are generally in accord with the qualitative prediction. Unusual effects may be seen in solvents of low dielectric constant where ion pairing is extensive, and we have already commented on the enhanced nucleophilic reactivity of anionic nucleophiles in dipolar aprotic solvents owing to their relative desolvation in these solvents. Another important class of ion-molecule reaction is the hydroxide-catalyzed hydrolysis of neutral esters and amides. Because these reactions are carried out in hydroxy lie solvents, the general medium effect is confounded with the acid-base equilibria of the mixed solvent lyate species. (This same problem occurs with Sn2 reactions in hydroxylic solvents.) This equilibrium is established in alcohol-water mixtures ... 

The notion of concurrent SnI and Sn2 reactions has been invoked to account for kinetic observations in the presence of an added nucleophile and for heat capacities of activation,but the hypothesis is not strongly supported. Interpretations of borderline reactions in terms of one mechanism rather than two have been more widely accepted. Winstein et al. have proposed a classification of mechanisms according to the covalent participation by the solvent in the transition state of the rate-determining step. If such covalent interaction occurs, the reaction is assigned to the nucleophilic (N) class if covalent interaction is absent, the reaction is in the limiting (Lim) class. At their extremes these categories become equivalent to Sn and Sn , respectively, but the dividing line between Sn and Sn does not coincide with that between N and Lim. For example, a mass-law effect, which is evidence of an intermediate and therefore of the SnI mechanism, can be observed for some isopropyl compounds, but these appear to be in the N class in aqueous media. 

Sn2 reactions are triggered by the collision of an alkyl halide with a nucleophile. 

Enhanced nucleophilicity is often correlated with more negative electrostatic potential. Which of the three molecules listed above is most nucleophilic according to this criterion Which is least nucleophilic (The least nucleophilic molecule does not, in fact, undergo Sn2 reactions.)... 

Another way to assess nucleophilic reactivity is to examii the shape of the nucleophile s electron-donor orbital (th is the highest-occupied molecular orbital or HOMC Examine the shape of each anion s HOMO. At which ato would an electrophile, like methyl bromide, find the be orbital overlap (Note This would involve overlap of tl the HOMO of the nucleophile and the lowest-unoccupif molecular orbital or LUMO of CH3Br.) Draw all of tl products that might result from an Sn2 reaction wi CHaBr at these atoms. 

Sn2 reactions proceed with inversion at the electrophilic carbon. This suggests that the nucleophile attacks from the backside of carbon, i.e., the side of carbon furthest away from the leaving group. 

Amines can be prepared by means of Sn2 reactions involving alkyl halides and nitrogen nucleophiles. 

The effect of a nitro group at the 6 position on the nucleophilic substitution reaction has been examined using l-methoxy-6-nitroindole (82) as a substrate (2001H1151). The reaction with NaOMe in refluxing DMF generates 6-nitroin-dole (83, 57%), 2-methoxy- (199, 22%), and 3-methoxy-6-nitroindoles (84, 6%) (Scheme 29). The formation of 199 and 84 can be explained by the SN2 -type nucleophilic substitution reaction at the 2 and 3 positions, respectively, with the... 

In contrast to S l reactions, the Sn2 type represent a one-step process. The rate-determining stage, and hence the formation of the new bond, depends on the nucleophilicity of the anion (the nucleo-philicity is essentially a function of the polarizability ). In the Sn2 reaction under discussion, Eq, (7), the nitrogen in CH3—is replaced by the atom of the mesomeric anion which possesses the greatest nucleophilicity. 

A mechanism that accounts for both the inversion of configuration and the second-order kinetics that are observed with nucleophilic substitution reactions was suggested in 1937 by E. D. Hughes and Christopher Ingold, who formulated what they called the SN2 reaction—short for substitution, nucleophilic, birnolecu-lar. (Birnolecular means that two molecules, nucleophile and alkyl halide, take part in the step whose kinetics are measured.)... 

The first SN2 reaction variable to look at is the structure of the substrate. Because the S, j2 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 a sterically hindered alkvl halide, whose carbon atom is "shielded" from approach of the incoming nucleophile, is higher in energy... 

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