Stereochemistry of nucleophilic substitution

Stereochemical courses of reactions will be expressed as percent inversion or retention of configuration with the difference from 100% understood to be racemization. 

Similarly, the stereochemistry of ethanolysis of 2-octyl tosylate was determined to be clean inversion of configuration  

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 5.14. Chiral 1-butanol-l-d 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 5.14 illustrates the stereospecific inversion observed in 1-butyl-1-d p-bromobenzenesulfonate, even toward nucleophiles as weak as formic acid. This inversion is indicative of a high degree of solvent participation in the displacement 

1 CH3CH2CH2CHDOBS Acetic acid, 99°C Formic acid, 99°C CH3CH2CH2CHDOAC CH3CH2CH2CHDOCHO 96 8% inversion 99 6% inversion b b 

2 (CH3)3CCHDOTs Sodium azide in hexa-methylphosphoramide, 90°C (CH3)3CCHDN3 98 2% inversion c 

Studies of the stereochemical course of nucleophilic substitution reactions have proven to be a powerul tool for consideration of mechanisms. As is always true, a proposed mechanism can never be established with complete certainty. The available data can be used only to suggest reasonable possibilities or to exclude mechanisms that are inconsistent with experimental facts. 

The method by which the stereochemical course of a nucleophilic substitution reaction is determined can be illustrated for the case of 2-octyl tosylate  

It should be noted that not all electron-attracting groups enhance reactivity. The sulfonyl and trifluoro groups, which cannot participate in this type of conjugation, retard the rate of Sn2 substitution at an adjacent carbon.  

The extent of the rate enhancement due to adjacent substituents is dependent on the nature of the transition state. The most important factor is the nature of the TT-type orbital which develops at the trigonal bipyramidal carbon in the transition state. If this carbon is cationic in character, electron donation from adjacent substituents becomes stabilizing. If bond formation at the transition state is far advanced, electron withdrawal should be more stabilizing. Substituents such as carbonyl therefore have their greatest effect on reactions with strong nucleophiles. Adjacent alkoxy substituents can stabilize Sn2 transition states that are cationic in character. Since the vinyl and phenyl groups can stabilize either type of transition state, the allyl and benzyl systems show enhanced reactivity toward both strong and weak nucleophiles.  

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleophilic substitution reactions. They are primary, and so do not readily form carbocation intermediates, but the t-butyl substituent effectively hinders back-side attack. The rate of reaction of neopentyl bromide with iodide ion is 470 times less than that of n-butyl bromide. Usually the neopentyl system reacts with rearrangement to the t-pentyl system. Use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. 

On the other hand, the primary benzyl system in entry 3 exhibits high, but not complete, inversion. This is attributed to racemization of the reactant by ionization and internal return. Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs with complete inversion. 

Studies of the stereochemical course of nucleophihc substitution reactions are a powerful tool for investigation of the mechanisms of these reactions. Bimolecular direct displacement reactions by the hmSN2 mechanism are expected to result in 100% inversion of configuration. The stereochemical outcome of the limS l ionization mechanism is less predictable because it depends on whether reaction occurs via one of the ion-pair intermediates or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of internal return. It is important to dissect the overall stereochemical outcome into the various steps of such reactions. 

Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs with complete inversion. The results cited in entry 5 serve to illustrate the importance of solvation of ion-pair intermediates in reactions of secondary substrates. The data show that partial racemization occurs in aqueous dioxane but that an added nucleophile (azide ion) results in complete inversion, both in the product resulting from reaction with azide ion and in the alcohol resulting from reaction with water. The alcohol of retained configuration is attributed to an intermediate oxonium ion resulting from reaction of the ion pair with the dioxane solvent. This would react with water to give product of retained configuration. When azide ion is present, dioxane does not effectively compete for the ion-pair intermediate, and all of the alcohol arises from the inversion mechanism.  

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 analysis, it can be determined that there is about 15% of rearrangement by hydride shift accompanying solvolysis in acetic acid. This increases to 35% in formic acid and 75% in trifluoroacetic acid. The extent of rearrangement increases with decreasing solvent 

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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... 

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. 

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. 

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. 

Stereochemistry of nucleophilic substitution at tetracoordinate silicon in Si,O-heterocycles 90CRV17. 

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. 

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... 

The mechanism and stereochemistry of nucleophilic substitution at silicon. We have already devoted two reviews to this topic (10, 11) but it seems appropriate here to discuss some new stereochemical aspects and to focus on the most recent developments regarding the mechanisms of displacement. 

The mechanism and stereochemistry of nucleophilic substitution at silicon, including displacement of silyl ligands in silicon-transition metal complexes. 

Complexes in which an increase in the coordination number at silicon is achieved by intramolecular ring closure of chelating groups are particularly interesting in relation to the stereochemistry of nucleophilic substitution at silicon. In these compounds the donor atom may play the role of a captive nucleophile , and the nature and behaviour of the intramolecularly coordinated species serve as models for the properties of the intermediates or transition states participating in the substitution processes. 

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. ... 

In addition. Hall and Inch (1980b) have demonstrated that the overall stereochemistry of nucleophilic substitution may be complicated by secondary processes. Recyclization mechanisms (p. 158) readily compete with direet exoeyclie displacement, and may also result in phosphoryl group migration subsequent to initial ring eleavage (Harrison and Inch, 1979). Confusion due to competing pathways hinders rationalization of the observed overall stereochemistry and product distribution of nucleophilic substitution. 

Ayala L, Lucero CG, Romero JAC, Tabacco SA, Woerpel KA (2003) Stereochemistry of nucleophilic substitution reactitms depending upon substituent evidence for electrostatic stabilization of pseudoaxial conformers of oxocarbenium ions by heteroatom substituents. J Am Chem Soc 125 15521-15528... 

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. 

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