Nucleophilic substitution solvent role

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. 

An S Ar (nucleophilic substitution at aromatic carbon atom) mechanism has been proposed for these reactions. Both nonenzymatic and enzymatic reactions that proceed via this mechanism typically exhibit inverse solvent kinetic isotope effects. This observation is in agreement with the example above since the thiolate form of glutathione plays the role of the nucleophile role in dehalogenation reactions. Thus values of solvent kinetic isotope effects obtained for the C13S mutant, which catalyzes only the initial steps of these reactions, do not agree with this mechanism. Rather, the observed normal solvent isotope effect supports a mechanism in which step(s) that have either no solvent kinetic isotope effect at all, or an inverse effect, and which occur after the elimination step, are kinetically significant and diminish the observed solvent kinetic isotope effect. 

The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 5 of Part A. That mechanistic understanding has contributed to the development of nucleophilic substitution reactions as importantl synthetic processes. The SN2 mechanism, because of its predictable stereochemistry and avoidance of carbocation intermediates, is the most desirable substitution process from a synthetic point of view. This section will discuss the role of SN2 reactions in the preparation of several classes of compounds. First, however, the important role that solvent plays in SN2 reactions will be reviewed. The knowledgeable manipulation of solvent and related medium effects has led to significant improvement of many synthetic procedures that proceed by the SN2 mechanism. 

The use of solvent isotope effects in studies of reaction mechanism and the theoretical interpretation of the kinetic effect of replacing H2 O by D20 have been thoroughly described [122, 123, 204, 211], Results for reactions involving proton transfer to and from carbon [122, 123, 204] have played a major role in the development of the fractionation factor theory for explaining solvent isotope effects, but other reactions [211(b), 211(c)], for example, nucleophilic substitution at saturated carbon, have also been well studied. In this section it will be shown how detailed information about a proton transfer transition state can be obtained by studying the solvent isotope effect for a reaction with known mechanism. Reactions with the A—SE2 mechanism will be discussed since this probably represents the most widely studied example of the application of solvent isotope effects in proton transfer to and from carbon [42, 47, 122,123, 204, 211(a), 212],... 

In addition to enantiocontrol, the problem of regiocontrol arises in these reactions. There are various factors that influence the regioselectivity of allylic substitutions [3,4,13, 36, 37, 38, 39]. Electronic effects exerted by the catalyst and the allylic substituents, steric interactions between the nucleophile, the allyl system and the catalyst, and the relative stabilities of the Ti-olefin complexes formed after nucleophilic addition, can all play a role. The relative importance of these factors varies with the catalyst, the substrate, the nucleophile, the solvent and other reaction parameters and is difficult to predict. 

The solvent in which nucleophilic substitutions are carried out has a marked effect on relative nucleophilicities. For a fuller understanding of the role of the solvent, let us consider nucleophilic substitution reactions carried out in polar aprotic solvents and in polar protic solvents. An organizing principle for substitution reactions is the following ... 

The result, a salt of the [FeHs]" anion with four [MgBr]" cations, is a crystalline yellow solid that is soluble in tetrahydrofuran to the extent of 0.006 M. The bromide atoms in the [MgBr] cations can be displaced by other good nucleophiles. Substitution of the bromide with tert-butoxide enhances the solubility in tetrahydrofuran to about 0.5 M and also increases solubdity in other less polar organic solvents. The complex hydride is capable of hydrogenating olefins and arenes under hydrogen. Recent interest has focused on the role of [FeHg] as a precursor for iron nanoparticles. ... 

How can these trends be explained An important consideration is the interaction of the solvent methanol with the anionic nucleophile. We have largely ignored the solvent in our discussion of organic reactions so far, in particular, radical halogenations (Chapter 3), in which they play an insignificant role. Nucleophilic substitution features polar starting materials and a polar mechanism, and the nature of the solvent becomes more important. Let us see how the solvent can become involved. 

Until now, we have not paid much attention on the tole of the solvent in nucleophilic substitution teac-tions, but the choice of solvent can tip the balance in favot of one substitution mechanism ot anothet. We noted that secondaty haloalkanes can react by either an Sj l or an Sj 2 mechanism. In these cases, the polarity of the solvent plays an important role. The S l process forms a carbocation intermediate. Because a polar solvent stabilizes charged species better than a non polar solvent, a polar solvent increases the rate of Sj 1 reactions. Reactions that occur via an mechanism are also affected by solvent polarity,... 

The addition reactions discussed in Sections 4.1.1 and 4.1.2 are initiated by the interaction of a proton with the alkene. Electron density is drawn toward the proton and this causes nucleophilic attack on the double bond. The role of the electrophile can also be played by metal cations, and the mercuric ion is the electrophile in several synthetically valuable procedures.13 The most commonly used reagent is mercuric acetate, but the trifluoroacetate, trifluoromethanesulfonate, or nitrate salts are more reactive and preferable in some applications. A general mechanism depicts a mercurinium ion as an intermediate.14 Such species can be detected by physical measurements when alkenes react with mercuric ions in nonnucleophilic solvents.15 The cation may be predominantly bridged or open, depending on the structure of the particular alkene. The addition is completed by attack of a nucleophile at the more-substituted carbon. The nucleophilic capture is usually the rate- and product-controlling step.13,16... 

For the methyl-substituted ethylenes, i.e. in the absence of any steric effects, there is a roughly linear relationship between the chemoselectivity and the 13C nmr chemical shift of the most substituted carbon atom of the bromonium ions (Dubois and Chretien, 1978). This selectivity is therefore discussed in terms of the magnitude of the charge on the carbon atom and the relative hardness of the competing nucleophiles, according to Pearson s theory (Ho, 1977). However, this interpretation does not take into account the substituent dependence of the nucleophilic solvent assistance, which must play a role in determining this chemoselectivity. 

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