Application Useful SN2 Reactions

Nucleophilic substitution by an Sn2 mechanism is common in the laboratory and in biological 

Nucleophilic substitution reactions are important in biological systems as well. The most common reaction involves nucleophilic substitution at the CH3 group in 5-adenosylmethionine, or SAM. SAM is the cell s equivalent of CH3I. The many polar functional groups in SAM make it soluble in the aqueous environment in the cell. 

a nutritional supplement sold under the name SAMe (pronounced sammy), has been used in Europe to treat depression and arthritis for over 20 years. In cells, 

SAM is used in nucleophilic substitutions that synthesize key amino acids, hormones, and neurotransmitters. 

In both examples, the initial substitution product bears a positive charge and goes on to lose a proton to form the product drawn. 

Two energy diagrams depicting the effect of steric hindrance in Sn2 reactions 

CHgBr is an unhindered alkyl halide. The transition state in the S 2 reaction is lower in energy, making Eg lower and increasing the reaction rate. 

Problem 7.22 Which compound in each pair undergoes a faster Sn2 reaction  

Problem 7.23 Explain why (CH3)3CCH2Br, a 1° alkyl halide, undergoes Sn2 reactions very slowly. 

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We have described a mixed MOVB model for describing the potential energy surface of reactive systems, and presented results from applications to SN2 reactions in aqueous solution. The MOVB model is based on a BLW method to define diabatic electronic state functions. Then, a configuration interaction Hamiltonian is constructed using these diabatic VB states as basis functions. The computed geometrical and energetic results for these systems are in accord with previous experimental and theoretical studies. These studies show that the MOVB model can be adequately used as a mapping potential to derive solvent reaction coordinates for... 

Alkylamines have a variety of applications in the chemical industry as starting materials for the preparation of insecticides and pharmaceuticals. Labetalol, for instance, a so-called /3-blocker used for the treatment of hi h blood pressure, is prepared by SN2 reaction of an epoxide with a primary amine. The substance marketed for drug use is a mixture of all four possible stereoisomers, but the biological activity derives primarily from the (R,R) isomer. 

Additions of oxygen and nitrogen nucleophiles to vinyloxiranes can be achieved with Pd(0) catalysis [103, 104]. Acetate, silanols, amines, sulfonamides, and azide have been used as nucleophiles, and the stereochemical outcome of these additions, where applicable, is normally the result of two consecutive SN2 reactions. This is demonstrated by the additions of NaNHTs to vinylepoxides 29 and 30, affording syn- and anti-amino alcohols 31 and 32, respectively, in good yields and with high diastereoselectivities (Scheme 9.22) [105]. 

The attack of the nucleophile on the acceptor-substituted allene usually happens at the central sp-hybridized carbon atom. This holds true also if no nucleophilic addition but a nucleophilic substitution in terms of an SN2 reaction such as 181 — 182 occurs (Scheme 7.30) [245]. The addition of ethanol to the allene 183 is an exception [157]. In this case, the allene not only bears an acceptor but shows also the substructure of a vinyl ether. A change in the regioselectivity of the addition of nucleophilic compounds NuH to allenic esters can be effected by temporary introduction of a triphenylphosphonium group [246]. For instance, the ester 185 yields the phos-phonium salt 186, which may be converted further to the ether 187. Evidently, the triphenylphosphonium group induces an electrophilic character at the terminal carbon atom of 186 and this is used to produce 187, which is formally an abnormal product of the addition of methanol to the allene 185. This method of umpolung is also applicable to nucleophilic addition reactions to allenyl ketones in a modified procedure [246, 247]. 

A model similar to that used for SN2 reactions has been advanced by Asubiojo and Brauman (1979) to account for the different aspects of reaction (67), and this model (68) is probably applicable to all systems discussed at the... 

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 second approach for the nucleophilic animation reactions to be considered here will be reactions of allyl halides and allyl acetates leading to allyl amines. Allyl halides are normally very reactive in SN2 reactions, but the direct coupling of allyl halides with nitrogen nucleophiles has been performed with limited success [4], as di- and trialkylated by products often predominate. The application of the Gabriel synthesis can to a certain extent eliminate the problem with polyalkylation of amines using, e.g., the stabilized phthalimide anion 19 as the nucleophile. The allyl amine 20... 

In addition to the application of SnI reactions as model reactions for the evaluation of solvent polarity, Drougard and Decroocq [48] suggested that the value of Ig kj for the Sn2 Menschutkin reaction of tri-n-propylamine and iodomethane at 20 °C -termed according to Eq. (7-21) - should also be used as a general measure of solvent polarity. 

AIMD is still a very time-consuming simulation method, and has so far mainly been used to study the stracture and dynamics of bulk water,as well as proton transfer and simple Sn2 reactions in bulk water.AIMD simulations are as yet limited to small system sizes and real simulation times of not more than a few picoseconds. However, some first applications of this technique to interfacial systems of interest to electrochemistry have appeared. There is no doubt that AIMD simulations of electrochemical interfaces will become increasingly important in the future, and some interesting first results will be described in Sections HI.7 and HI.8. 

To decipher this complexity, electrochemistry at the polarized liquid-liquid interface developed over the past two decades has been proven to be a powerful tool, as shown in elucidation of the mechanism of ion-pair extraction [1 ] and the response of ion-selective electrodes of liquid-membrane type to different types of ions [5 7]. Along this line, several attempts have been made to use polarized liquid liquid interfaces for studying two-phase Sn2 reactions [8-10], two-phase azo-coupling [11], and interfacial polymerizations [12]. Recently, kinetic aspects of complexation reactions in facilitated ion transfer with iono-phores and the rate of protonation of amines have been treated quantitatively [13-16]. Their theoretical framework, which was adapted from the theories of kinetic currents in polaro-graphy, can be directly applicable to analyze quantitatively the chemical reactions in the two-phase systems. In what follows is the introduction to recent advances in electrochemical studies of the chemical reactions at polarized liquid liquid interfaces, mainly focusing on... 

Warshel and co-workers > ° >i studied the dynamics of this Sn2 reaction using an interesting and different approach the empirical valence bond (EVB) method, which has been described in detail in a recent book by Warshel. The fundamental idea behind the application of the EVB method to this Sn2 reaction is that the reaction can be treated as a two state system, where the reactants and products are each taken to be separate quantum mechanical states with Hamiltonians and Hi- These states can be coupled together by an empirical coupling Hamiltonian so that when the two state Hamiltonian is diagonalized, the correct features of the ground state surface on which the reaction occurs are obtained. H, and H2 are taken by Warshel and coworkers to have analytic forms based on the gas phase parameters. 

This work has indicated that VTST may be a useful method for calculating solution rate constants and thereby helping to understand solution reaction dynamics through analysis of the solution transition state surface. However, for this to occur, a simple prescription must be developed for applying VTST to solution systems where full molecular dynamics can be performed, much in the way that Grote-Hynes theory has been used to understand a wide variety of molecular dynamics results. Work by Hahn and Pollak o is proceeding in this direction through the application of VTST to the Cl -I- CHjCI Sn2 reaction in aqueous solution discussed elsewhere in this review.(A closely related study is the VTST work by Tucker and Truhlar on the mono- and dihydrated versions of this S 2 reaction.)... 

Our goal is not to study just the SnI reaction of t-BuCl, but instead to apply the LFER to many different reactions. Hence, an LFER with a sensitivity factor m for any new reaction under study is used (Eq. 8.39). Here, k evi is the rate constant for the new reaction in various solvents. The reference solvent is still 80% ethanol. Although the majority of the studies using this equation have been SnI and Sn2 reactions (see examples in Chapter 11), it is in principle applicable to any reaction. 

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