The Sn2 Mechanism of Nucleophilic Substitution

Although the alkyl halide and alcohol given in this example have opposite configurations when they have opposite signs of rotation, it cannot be assumed that this will be true for all alkyl halide/ alcohol pairs. 

This stereochemical fact comes from studies of nucleophilic substitutions of optically active alkyl halides. In one such experiment, Hughes and Ingold determined that the reaction of optically active 2-bromooctane with hydroxide ion gave 2-octanol, having the opposite configuration at its chirality center. 

Nucleophilic substitution had occurred with inversion of configuration, consistent with the following transition state  

The Fischer projection for (+)-2-bromooctane is shown. Write the Fischer projection of the H-2-octanoi formed from it by the Sn2 mechanism. 

Would you expect the 2-octanol formed by Sn2 hydrolysis of ( )-2-bromooctane to be optically active If so, what will be its absolute configuration and sign of rotation What about the 2-octanol formed by hydrolysis of racemic 2-bromooctane  

The mechanisms by which nucleophilic substitution takes place have been the subject of much study. Extensive research by Sir Christopher Ingold and Edward D. Hughes and their associates at University College, London, during the 1930s emphasized kinetic and stereochemical measurements to probe the mechanisms of these reactions. 

Kinetics. Kinetic studies measure the speed of a reaction, especially with respect to how the concentration of reactants (and catalysts, if any) affect the reaction rate. Having already seen that the rate of nucleophilic substitution depends on the leaving group (I Br Cl F), we know that the carbon-halogen bond must break in the slow step of the reaction. Consequently, we expect that the reaction rate will depend on the concentration of the alkyl halide. This is confirmed by kinetic studies of the reaction 

The relationship between leaving-group ability and basicity is explored in more detail in Section 8.12 

The reaction rate is directly proportional to the concentration of both methyl bromide and hydroxide ion. It is first order in each reactant, or second order overall. The most reasonable conclusion is that both hydroxide ion and methyl bromide react together in a bimolecular elementary step and that this step is rate-determining. 

THE MECHANISM The reaction proceeds in a single step. Hydroxide ion acts as a nucleophile. While the C—Br bond is breaking, the C—O bond is forming. 

Recall that the term kinetics refers to how the rate of a reaction varies with changes in concentration. Consider the nucleophilic substitution in which sodium hydroxide reacts with methyl bromide to form methyl alcohol and sodium bromide  

Hughes and Ingold interpreted second-order kinetic behavior to mean that the ratedetermining step is bimolecular, that is, that both hydroxide ion and methyl bromide are involved at the transition state. The symbol given to the detailed description of the mechanism that they developed is Sn2, standing for substitution nucleophilic bimolecular. 

Carbon is partially bonded to both the incoming nucleophile and the departing hahde at the transition state. Progress is made toward the transition state as the nucleophile begins to share a pair of its electrons with carbon and the halide ion leaves, taking with it the pair of electrons in its bond to carbon. 

---

This process occurs as a concerted reaction, is stereospecific, and thus corresponds to the Sn2 mechanism of nucleophilic substitution at an sp -C-atom. For example, from ds-2,3-dimethy-l-oxirane, ( )-threo3-aminobutan-2-ol is obtained by reaction with NH3 ... 

These sections show how a variety of experimental observations led to the proposal of the SN1 and the SN2 mechanisms for nucleophilic substitution. Summary Table 8.9 integrates the material in these sections. 

The role of nitronium ion in the nitration of benzene was demonstrated by Sir Christopher Ingold—the same person who suggested the SN1 and Sn2 mechanisms of nucleophilic substitution and who collaborated with Cahn and Prelog on the ft and S notational system. 

Generally the nucleophilic substitution of primary alkyl halides will occur via the SN2 mechanism, whereas nucleophilic substitution of tertiary alkyl halides will occur by the SN1 mechanism. Generally secondary alkyl halides are more likely to react by the SN2 mechanism, but it is not possible to predict this with certainty. 

The two main mechanisms for nucleophilic substitution of alkyl halides are SN1 and SN2. These represent the extreme mechanisms of nucleophilic substitution, and some reactions involve mechanisms which lie somewhere in between the two. 

Two mechanisms of isotopic exchange in alcohols can he considered, corresponding to the SN1 and SN2 mechanisms of nucleophilic substitution. Water is the nucleophile in this case, attacking a saturated carbon atom. In all the studies reported so far, exchange occurs only in acid solution and it has always been assumed that the conjugate acid of the alcohol is the reacting species. 

The points we have emphasized in this brief overview of the SnI and Sn2 mechanisms are kinetics and stereochemistry. These have often been important pieces of evidence in ascertaining whether a particular nucleophilic substitution follows an ionization or direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the SnI mechanism and those exhibiting second-order kinetics react by the Sn2 mechanism. Many nucleophilic substitutions are carried out under conditions in which the nucleophile is present in large excess. When this is the case, the concentration of the nucleophile is essentially constant during the reaction and the observed kinetics will become pseudo-first-order. This will be true, for example, when the solvent is the nucleophile. In this case, the kinetics of the reaction will provide no evidence as to whether the SnI or Sn2 mechanism operates. 

A treatise on kinetics is a logical and fitting medium in which to analyze and discuss just such limitations and uncertainties of mechanism. The present chapter will attempt such a treatment for the SN2 mechanism in nucleophilic aromatic substitution. An effort will be made to pinpoint every assumption and highlight every instance where alternate choices are possible. The end result hoped for is a clearer delineation of the known and the probable from the uncertain and the unknown. 

This intermediate is similar to those encountered in the neighboring-group mechanism of nucleophilic substitution (see p. 404). The attack of W on an intermediate like 2 is an Sn2 step. Whether the intermediate is 1 or 2, the mechanism is called AdE2 (electrophilic addition, bimolecular). 

The basic classification of nucleophilic substitutions is founded on the consideration that when a new metal complex is formed through the breaking of a coordination bond with the first ligand (or water) and the formation of a new coordination bond with the second ligand, the rupture and formation of the two bonds can occur to a greater or lesser extent in a synchronons manner. When the mpture and the formation of the bonds occur in a synchronous way, the mechanism is called substitution nucleophilic bimolecular (in symbols Sn2). On the other extreme, when the rupture of the first bond precedes the formation of the new one, the mechanism is called substitution nucleophilic unimolecular (in symbols SnI). Mechanisms Sn2 and SnI are only limiting cases, and an entire range of intermediate situations exists. 

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. 

Like halides, the tosylate leaving group is displaced by a wide variety of nucleophiles. The Sn2 mechanism (strong nucleophile) is more commonly used in synthetic preparations than the SN1. The following reactions show the generality of SN2 displacements of tosylates. In each case, R must be an unhindered primary or secondary alkyl group if substitution is to predominate over elimination. 

Many radical cations derived from cyclopropane (or cyclobutane) systems undergo bond formation with nucleophiles, typically neutralizing the positive charge and generating addition products via free-radical intermediates [140, 147). In one sense, these reactions are akin to the well known nucleophilic capture of carbocations, which is the second step of nucleophilic substitution via an Sn 1 mechanism. The capture of cyclopropane radical cations has the special feature that an sp -hybridized carbon center serves as an (intramolecular) leaving group, which changes the reaction, in essence, to a second-order substitution. Whereas the SnI reaction involves two electrons and an empty p-orbital and the Sn2 reaction occurs with redistribution of four electrons, the related radical cation reaction involves three electrons. 

---