Stereochemistry nucleophilic substitution

An advantage that sulfonate esters have over alkyl halides is that their prepara tion from alcohols does not involve any of the bonds to carbon The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group Thus the configuration of a sulfonate ester is exactly the same as that of the alcohol from which It was prepared If we wish to study the stereochemistry of nucleophilic substitution m an optically active substrate for example we know that a tosylate ester will have the same configuration and the same optical purity as the alcohol from which it was prepared... 

Illustrate the stereochemistry associated with unimolecular nucleophilic substitution by con structmg molecular models of cis 4 tert butylcyclohexyl bromide its derived carbocation and the alcohols formed from it by hydrolysis under S l conditions... 

The points that we have emphasized in this brief overview of the S l and 8 2 mechanisms are kinetics and stereochemistry. These features of a reaction provide important evidence for ascertaining whether a particular nucleophilic substitution follows an ionization or a direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the Sj l mechanism and those exhibiting second-order kinetics react by the 8 2 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 die reaction and the observed kinetics become pseudo-first-order. This is true, for example, when the solvent is the nucleophile (solvolysis). In this case, the kinetics of the reaction provide no evidence as to whether the 8 1 or 8 2 mechanism operates. 

Nucleophilic substitution in cyclohexyl systems is quite slow and is often accompanied by extensive elimination. The stereochemistry of substitution has been determined with the use of a deuterium-labeled substrate (entry 6). In the example shown, the substitution process occurs with complete inversion of configuration. By NMR amdysis, it can be determined that there is about 15% of rearrangement by hydride shift accon any-ing solvolysis in acetic acid. This increases to 35% in formic acid and 75% in trifiuoroacetic acid. The extent of rearrangement increases with decreasing solvent... 

The first three chapters discuss fundamental bonding theory, stereochemistry, and conformation, respectively. Chapter 4 discusses the means of study and description of reaction mechanisms. Chapter 9 focuses on aromaticity and aromatic stabilization and can be used at an earlier stage of a course if an instructor desires to do so. The other chapters discuss specific mechanistic types, including nucleophilic substitution, polar additions and eliminations, carbon acids and enolates, carbonyl chemistry, aromatic substitution, concerted reactions, free-radical reactions, and photochemistry. 

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. 

How- does this reaction take place Although it appears superficially similar to the SN1 and S 2 nucleophilic substitution reactions of alkyl halides discussed in Chapter 11, it must be different because aryl halides are inert to both SN1 and Sj 2 conditions. S l reactions don t occur wdth aryl halides because dissociation of the halide is energetically unfavorable due to tire instability of the potential aryl cation product. S]sj2 reactions don t occur with aryl halides because the halo-substituted carbon of the aromatic ring is sterically shielded from backside approach. For a nucleophile to react with an aryl halide, it would have to approach directly through the aromatic ring and invert the stereochemistry of the aromatic ring carbon—a geometric impossibility. 

As previously mentioned, the nucleophilic substitution on the Mo complex 71 most likely occurs with retention of configuration based on the stereochemistry outcomes of the product and 71. The retention-retention mechanism was confirmed with labeling experiments in collaboration with Professor Lloyd-Jones, as shown in Scheme 2.25 [27]. 

A combination of a Pd-catalyzed nucleophilic substitution by a phenol and a ring expansion was described by Ihara and coworkers [127] using cis- or trans-substituted propynylcyclobutanols 6/l-262a or 6/l-262b. The product ratio depends on the stereochemistry of the cyclobutanols and the acidity of the phenol 6/1-263. Thus, reaction of 6/l-262b with p-methoxyphenol 6/1-263 (X = pOMe) led exclu-... 

Chiral sulfonium ylides have been known for some 30 years, and their stereochemistry and properties have been studied.15 Optically active selenonium ylides were obtained by reacting selenoxides with 1,3-cyclohexanedione under asymmetric conditions by Sakaki and Oae in 1976 for the first time,16 and also optically resolved by fractional recrystallization of the diastereomeric mixtures in the early 1990s.17 In 1995, optically active selenonium ylides 6 were obtained in over 99% de by nucleophilic substitution of optically active chloroselenurane or selenoxide with active methylene compounds with retention of configuration.18 The absolute configurations were determined by X-ray analysis of one... 

Here we have a c = c group attached to a carbon atom which is adjacent to be carbon atom where nucleophilic substitution can occur and during the course of the reaction becomes bonded of partially bonded to the reaction centre to form a non-classical or bridged ion (Fig. 1 to 1(c)). Thus the rate and/or the stereochemistry may be affected. This explains why the acetolysis of 5 is 1011 times faster than that of 5(a), because it involves the formation of a non-classical carbocation... 

Reactivity toward nucleophiles and comparison with other electrophilic centers 152 Paths for nucleophilic substitution of sulfonyl derivatives 156 Direct substitution at sulfonyl sulfur stereochemistry 157 Direct substitution at sulfonyl sulfur stepwise or concerted 158 The elimination-addition path for substitution of alkanesulfonyl derivatives 166 Homolytic decomposition of a-disulfones 172 10 Concluding remarks 173 Acknowledgement 174 References 174... 

Reaction of a sulfinyl sulfone with a nucleophile in the manner shown in (139) is, of course, an example of a nucleophilic substitution at sulfinyl sulfur. Reactions of this general type occur frequently and are of great importance in the chemistry of most kinds of sulfinic acid derivatives. At this point it would seem desirable to discuss what is known about such key aspects of their mechansim as stereochemistry and the timing of the bond-making and bond-breaking processes necessary in such a substitution. In doing this we will call upon results obtained from the study of such reactions using a variety of different types of sulfinic acid derivatives. 

Independent evidence for backside attack in gas-phase acid-induced nucleophilic substitutions was provided by a number of studies, carried out using stationary radiolysis." Further confirmation was provided by Morton and coworkers," who investigated the stereochemistry of the proton-induced nucleophilic substitution on (5)-(- -)- and (R)-(— )-2-butanol in the gas-phase at 10 torr in their 70-eV EBF radiolysis reactor. In the presence of a strong base, i.e., tri-n-propylamine... 

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 replacement of the oxygen atom in sulfoxides by nitrogen leads to a new class of chiral sulfur compounds, namely, sulfimides, which recently have attracted considerable attention in connection with the stereochemistry of sulfoxide-sulfimide-sulfoximide conversion reactions and with the steric course of nucleophilic substitution at sulfur. The first examples of chiral sulfimides, 88 and 89, were prepared and resolved into enantiomers by Phillips (127,128) by means of the brucine and cinchonidine salts as early as 1927. In the same way, Kresze and Wustrow (129) were able to separate the enantiomers of other structurally related sulfimides. 

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. 

We hope that this review of chiral sulfur compounds will be useful to chemists interested in various aspects of chemistry and stereochemistry. The facts and problems discussed provide numerous possibilities for the study of additional stereochemical phenomena at sulfur. As a consequence of the extent of recent research on the application of oiganosulfur compounds in synthesis, further developments in the field of sulfur stereochemistry and especially in the area of asymmetric synthesis may be expected. Looking to the future, it may be said that the static and dynamic stereochemistry of tetra- and pentacoordinate trigonal-bipyramidal sulfur compounds will be and should be the subject of further studies. Similarly, more investigations will be needed to clarify the complex nature of nucleophilic substitution at tri- and tetracoordinate sulfur. Finally, we note that this chapter was intended to be illustrative, not exhaustive therefore, we apologize to the authors whose important work could not be included. 

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

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. 

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