Stereochemistry of nucleophilic substitution reactions

Part of the evidence for the existence of two possible mechanisms for nucleophilic substitution reactions is the kinetic order of the reaction (Section 9.9). We know an Sj 2 mechanism is a one-step process in which the nucleophile attacks the substrate and the leaving group departs simultaneously. In this concerted, bimolecular process, the substrate and the nucleophile are both present in the transition state. The rate of the reaction depends on the concentrations of both the nucleophile and the substrate. 

In other nucleophilic substitution reactions, the rate of the reaction depends only on the concentration of the substrate, not on that of the nucleophile. These imimolecular reactions, designated S l, occur in two steps. In the first step, the bond between the carbon atom and the leaving group breaks to produce a carbocation and a leaving group. In the second step, the carbocation reacts with the nucleophile to form the product. The first step in an S jl reaction, formation of a carbocation, is the slow, or rate-determining step. The second step, formation of a bond between the nucleophile and the carbocation, occurs very rapidly. Since the slow step of the reaction involves only the substrate, the reaction is a first-order process. 

Now we will consider important information about the chirality of the reactant and the product that also distinguishes between the Sj j2 and S l mechanisms. The stereochemical consequences of the two mechanisms differ because the transition states in the two mechanisms differ. In the Sj,j2 mechanism, the nucleophile and the substrate form a pentacovalent transition state in the shape of a trigonal bipyramid. In the 1 mechanism, when the leaving group departs, the resulting carbocation is a planar, sp -hybridized carbocation. 

Sterically hindered trigonal bipyramidal transition state an Sn2 reaction does not occur. 

If the hydroxide ion had bonded to the carbon atom on the side that was originally occupied by the leav-ing group, the product would have the same configuration as the reactant. This stereochemical process, termed retention of configuration, does not occur. 

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There are a number of synthetically important applications, involving these heterocycles, as unstable intermediates, which are reviewed here. These applications feature the ability of selenium to be readily extruded from seleniranes and selenirenes, neighboring group participation by / -Se to control the stereochemistry of nucleophilic substitution reactions, and facile, chemoselective replacement of Se by H in radical-induced reactions. 

Micellar control of the stereochemistry of nucleophilic substitution reactions was first recognized in die nitrous acid deamination of 2-aminooctanel91 Below the CMC of 2-octylammonium perchlorate, 2-octanol is formed with the inversion stereochemistry normally expected in the deamination of a 2-aminoalkane. With increasing concentration the percentage of inversion decreases to zero, after which retention of configuration occurs. The observed stereochemistry was demonstrated to... 

Solvolysis reactions in media of low nucleophilicity are characterized by increased tendencies toward carbonium ion rearrangements and increased racemiza-tion when optically active substrates are employed. We have seen examples of extensive rearrangements in our discussion of carbonium ions generated in superacid media, in which the observed ion was quite often the most stable possible ion of a particular system. A later section of this chapter deals with the stereochemistry of nucleophilic substitution reactions, and examples of solvent nucleophilicity effects on stereochemistry will be encountered there. 

The stereochemistry of nucleophilic substitution reactions has been examined for substrates ranging in complexity from primary alkyl to triarylmethyl. A summary of representative examples is presented in Table 5.12. Chiral 1-butanol-l-rf and its derivatives have small, but measurable, optical rotations and provide useful substrates for the important case of substitution in primary systems. Entry 1 in Table 5.12 illustrates the stereospecific inversion observed in 1-butyl-1-rf... 

However, the major factor stimulating the rapid development of static and dynamic sulfur stereochemistry was the interest in the mechanism and steric course of nucleophilic substitution reactions at chiral sulfur. Very recently, chiral organic sulfur compounds have attracted much attention as useful and efficient reagents in asymmetric synthesis. 

The most frequently encountered reactions in organic sulfur chemistry are nucleophilic displacement reactions. The mechanism and steric course of reactions have been the main points of interest of research groups all over the world, in particular, Andersen, Cram, Johnson, and Mislow in the United States Kobayashi and Oae in Japan Kjaer in Denmark and Fava and Montanari in Italy. The results of these investigators have been discussed exhaustively in many reviews on sulfur stereochemistry. In a recent report on nucleophilic substitution at tricoordinate sulfur, the literature was covered by Tillett (10) to the end of 1975. Therefore only some representative examples of nucleophilic substitution reactions at chiral sulfur are discussed here. However, recent results obtained in the authors laboratory are included. 

In contrast to the widely investigated stereochemistry of nucleophilic substitution at optically active tricoordinate sulfur, there have been few similar studies with optically active tetracoordinate sulfur systems. Sabol and Andersen (174) were the first to show that the reaction of p-tolylmagnesium bromide with (-)-menthyl phenyl-methane[ 0- 0]sulfonate 140 proceeds with inversion of configuration. Thus, the Grignard reaction at the sulfinyl and sulfonyl centers takes place with the same stereochemistry. 

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. 

Recently, the stereochemistry of nucleophilic substitution at silicon has been reviewed by Holmes2, and the role of pentacoordinate silicon compounds as reaction intermediates has been reviewed by Corriu and coworkers3. 

The most common nucleophiles in 8 2 reactions bear a net negative charge. The most common nucleophiles in 8 1 reactions are weak nucleophiles such as H2O and ROH. The identity of the nucleophile is especially important in determining the mechanism and therefore the stereochemistry of nucleophilic substitution when 2° alkyl halides are starting materials. 

The stereochemical course of nucleophilic substitution reactions is best illustrated by reference to substitution at a saturated carbon atom. The underlying principles of these reactions are fundamental to an understanding of the more complex stereochemistry of iSn reactions on steroids, carbohydrates and vinyl compounds which are considered in detail in the relevant sections below. 

A mechanism that accounts for both the stereochemistry and the kinet ics of nucleophilic substitution reactions was suggested in 1937 by E. D... 

Studies of the stereochemistry are a powerful tool for investigation of nucleophilic substitution reactions. Direct displacement reactions by the Sjv2(lim) mechanism are expected to result in complete inversion of configuration. The stereochemical outcome of the ionization mechanism is less predictable, because it depends on whether reaction occurs via an ion pair intermediate or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of ion pair recombination. 

The extensive review of Hall and Inch (1980b) on the stereochemistry of nucleophilic substitution at phosphorus indicates that a lack of stereospecificity is the rule rather than the exception in the presence of a six-membered ring. They have bravely attempted to define trends in specific six-membered systems, but are forced to conclude that ... the incorporation of phosphorus into a six-membered ring, in itself, provides no overriding influence on reaction. ... 

It is important to note that formation of the sulfonate ester does not affect the stereochemistry of the alcohol carbon, because the C — O bond is not involved in this step. Thus, if the alcohol carbon is a chirality center, no change in configuration occurs on making the sulfonate ester—the reaction proceeds with retention of configuration. On reaction of the sulfonate ester with a nucleophile, the usual parameters of nucleophilic substitution reactions become involved. 

The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 5, Part A. That mechanistic basis has contributed to the development of nucleophilic substitution reactions as important synthetic processes. The Sn2 mechanism, because of its predictable stereochemistry and avoidance of... 

What product would you expect from a nucleophilic substitution reaction of (R)-l-bromo-l-phenylethane with cyanide ion, C=N, as nucleophile Show the stereochemistry of both reactant and product, assuming that inversion of configuration occurs. 

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