SN2 Reactions in Solution

Spectrophotometric data for the Sn2 reaction between p-nitrophenoxide (PNPO) and methyl iodide in acetonitrile (containing 0.04% water) was observed to deviate from that expected for the simple single-step mechanism generally believed for Sn2 reactions in solution. The experimental data 

CI /CHjBr Halide Exchange Reaction F / CH,CI Halide Exchange Reaction 

The latter brings out a very important mechanistic point. A recent paper in which the 2003 work is not referred to, treats the gas-phase Sn2 mechanism as the double potential energy well model while still asserting that the solution-phase reaction corresponds to the single-step 

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For Sn2 reactions in solution, there are four main principles that govern the effect of the nucleophile on the rate, though the nucleophilicity order is not invariant but depends on substrate, solvent, leaving group, and so on. 

A well-known feature of SN2 reactions in solutions is the high sensitivity to steric effects. For example, the relative rates in acetone solution for reaction (29) suffer dramatic changes in going fromR = CH3 (A rel = 1) through C2H5... 

The Sn2 reaction in solution. We saw above the application of microsolvation to Sn2 reactions ([14, 15]). Let us now look at the chloride ion-chloromethane Sn2 reaction in water, as studied by a continuum method. Figure 8.2 shows a calculated reaction profile (potential energy surface) from a continuum solvent study of the Sn2 attack of chloride ion on chloromethane (methyl chloride) in water. Calculations were by the author using B3LYP/6-31+G (plus or diffuse functions in the basis set are considered to be very important where anions are involved Section 5.3.3) with the continuum solvent method SM8 [22] as implemented in Spartan [31] some of the data for Fig. 8.2 are given in Table 8.1. Using as the reaction coordinate r the deviation from the transition state C-Cl... 

The determination of potentials of mean force has, e.g., been applied to nucleophilic substitution (Sn2) reactions in solution, as illustrated in Example 10.1. 

Dissociation ofY-R—X in step 4 (Eqn (1.13)) completes the forward reaction. Steps 1 and 4 are reversible so the reaction is an equilibrium and the composition of the mixture wiU depend upon the energetics of the system. In the gas phase, the double potential energy wells lie at lower energy than either the reactants or the products. Recent computations in solution suggest that Eqns (1.10)-(1.13) hold for the Sn2 reactions in solution as well. 

This raises a point that connects these studies of solvation dynamics with general theories of reactivity. It has been pointed out that the energy changes associated with solvation changes on this time-scale are important in, for example, Sn2 reactions in water they increase the rate of reaction, by stabilising the product. The usual theory of Sn2 reactions in solution assumes that there is equilibrium solvation at all points on the reaction coordinate, implying that the reorientation of solvent molecules is very fast compared with motion along the reaction coordinate. The ultrafast motion of water molecules just described sup-... 

Nucleophilic displacement reactions, reactions that formally also involve the transfer of R+, have been explored in great depth in the gas phase with the majority of available mass spectrometric techniques. In part this has been because of the importance of Sn2 reactions in solution chemistry and their extreme sensitivity to solvent, both in solution and in the gas phase. Unsolvated 5 2 reactions are characterized by double minima in the reaction energy profile as shown in Figure 1 and the following reaction mechanism ... 

PEP theory has also been applied to modelling the free energy profiles of reactions in solution. An important example is the solvent effect on the SN2 reaction... 

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 above results pertain to reactions in solution. In the gas phase reactions can take a different course, as illustrated by the reaction of carboxylic esters with MeO, which in the gas phase was shown to take place only by the Bal2 mech-anism, ° even with aryl esters, ° where this means that an Sn2 mechanism takes place at an aryl substrate. However, when the gas-phase reaction of aryl esters was carried out with MeO ions, each of which was solvated with a single molecule of MeOH or H2O, the Bac2 mechanism was observed. 

In proposed mechanism I, the loss of water from the complex is the rate-determining step, but removal of water from the coordination sphere of the metal ion should be independent of the nature of the anion that is not part of the coordination sphere of the metal ion. On the other hand, if mechanism II is correct, the entry of X into the coordination sphere of the metal would be dependent on the nature of the anion, because different anions would be expected to enter the coordination sphere at different rates. Because there is an observed anion effect, it was concluded that the anation reaction must be an Sn2 process. However, it is not clear how a process can be "second-order" when both the complex cation and the anion are parts of the same formula. As discussed in Chapter 8, it is not always appropriate to try to model reactions in solids by the same kinetic schemes that apply to reactions in solutions. 

The first microscopical computation of a free energy curve for a chemical reaction in solution was performed by the Jorgensen s group [41,52,53] ten years ago. They studied the degenerate SN2 reaction of chloride anion with methyl chloride in gas phase, in aqueous solution and in dimethylformamide (DMF) ... 

Aguilar, M., Bianco, R., Miertus, S., Persico, M. and Tomasi, J. Chemical reactions in solution modeling of the delay of solvent synchronism (dielectric friction) along the reaction path of an SN2 reaction, Chem. Phys., 174(1993), 397-407... 

Abstract This chapter describes a number of examples of kinetic isotope effects on chemical reactions of different types (simple gas phase reactions, Sn2 and E reactions in solution and in the gas phase, a and 3 secondary isotope effects, etc.). These examples are used to illustrate many aspects of the measurement, interpretation, and theoretical calculation of KIE s. The chapter concludes with an example of an harmonic semiclassical calculation of a kinetic isotope effect. 

In this article, we present an ab initio approach, suitable for condensed phase simulations, that combines Hartree-Fock molecular orbital theory and modem valence bond theory which is termed as MOVB to describe the potential energy surface (PES) for reactive systems. We first provide a briefreview of the block-localized wave function (BLW) method that is used to define diabatic electronic states. Then, the MOVB model is presented in association with combined QM/MM simulations. The method is demonstrated by model proton transfer reactions in the gas phase and solution as well as a model Sn2 reaction in water. 

The above model has been further explored to account for reaction efficiencies in terms of a scheme where nucleophilicities and leaving group abilities can be rationalized by a structure-reactivity pattern. Pellerite and Brau-man (1980, 1983) have proposed that the central energy barrier for an exothermic reaction (see Fig. 3) can be analysed in terms of a thermodynamic driving force, due to the exothermicity of the reaction, and an intrinsic energy barrier. The separation between these two components has been carried out by extending to SN2 reactions the theory developed by Marcus for electron transfer reactions in solutions (Marcus, 1964). While the validity of the Marcus theory to atom and group transfer is open to criticism, the basic assumption of the proposed model is that the intrinsic barrier of reaction (38)... 

SAMPLE SOLUTION 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. 

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]. 

Chemical reaction in solution phase is of great importance not only in its universality as an environment of reactions but also in understanding the solvation effect on the solute electronic structure. SN2 reaction in aqueous solution,... 

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