Stereochemical course of nucleophilic substitution reactions

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 

Secondary 4 CH3CH(CH2)5CH3 OTs Sodium acetate in acetic acid, steam bath CH3CH(CH2)5CH3 OAc 65% inversion e 

but not 100%, inversion of configuration was observed in the acetolysis of chiral benzyl- 1-rf tosylate (entry 3). The decreased stereospecificity was attributed to racemization of the substrate under the reaction conditions. Substitution on benzyl tosylate may reasonably be expressed as proceeding via displacement on the substrate or intimate ion pair. 

Entry 4 presents an early result on the gross stereochemistry of acetolysis of 2-octyl tosylate. We have seen earlier that after correction for racemization of the substrate and the product and addition of acetic acid to octenes under the reaction conditions, the displacement step occurs stereospecifically with inversion. The results cited in entry 5 are important and illustrate the importance of solvation of the ion-pair intermediates in nucleophilic substitution reactions of secondary substrates. In aqueous dioxane, the ion-pair intermediate may be solvated by water molecules or by dioxane. Inverted product results from solvation by water, but solvation by dioxane cannot collapse to a stable product. Subsequent solvation steps can lead to symmetrical solvation or attack by water from the front side, displacing dioxane. The observed result is the formation of partially racemic 2-octanol  

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Table 5.16 Stereochemical Course of Nucleophilic Substitution Reactions...

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. 

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. 

All of the reactions so far mentioned involved as nucleophiles either organometallic reagents or one, PhNH-, that is much more basic than any of those in Table 6. That complete inversion is also the stereochemical course of a substitution involving a rather weak nucleophile has also been neatly demonstrated by Mikolajczyk et al. (1979). In the presence of a small amount of an acid catalyst optically active,, 4C-labeled methyl p-toluenesulfinate undergoes exchange with methanol as shown in (151), a process that also... 

Stereochemical course of the reaction. This kind of information was critical in the elucidation of the SnI and Sn2 pathways for nucleophilic substitution at saturated carbon. 

The cis- and frans-sulfoxides (551) and (552) have been O-methylated with Meerwein s reagent. Reaction of the methoxy derivative with MeMgBr proceeds with inversion of configuration (Scheme 211) (74JA8026). The stereochemical course of the interconversions of sulfoxide, sulfimide and sulfoximide in the 2,3-dihydrobenzo[6]thiophene series has been investigated (73JA1916). The reaction cycle (Scheme 212) involves both nucleophilic and electrophilic substitution at chiral sulfur. Inversion of configuration takes place in the conversion of (553) to (554) in pyridine. 

Hyperconjugation appears to be the dominant factor governing the diastereoselectivity of the hydrochlorination of 5-substituted 2-methyleneadamantanes 3 (Table 2)36. However, the product distribution for epoxidation suggests that the stereochemical course of electrophilic additions not mediated by carbocations is most likely regulated by direct field effects36. Note that, unlike in the previous reactions, the facial selectivity in this case reflects the preference for the nucleophilic attack on the corresponding carbocation. 

Although few investigations have been made to determine the stereochemical course of the reaction of Jt-allylmthenium complexes with nucleophiles, Harman and coworkers recently reported that the reaction with soft nucleophiles exclusively proceeded via an anti mechanism [58]. The observations described here, together with information in the literature, suggest that the ruthenium-catalyzed allylic substitution reaction proceeds via a double inversion (i.e., a net retention) mechanism. 

The mechanism of the reaction is well-known. The first step is formation of a carbanion, followed by nucleophile addition to the carbonyl carbon atom halo-hydrin alcoholates are produced finally, ring-closure takes place by intramolecular substitution. The stereochemistry of the reaction is much disputed the reason why a unified viewpoint has not emerged is that the configuration of the end-product is influenced by the structure of the starting compound (including steric hindrance), the base employed, and solvation by the solvent, sometimes in an unclear manner. The stereochemical course of the reaction is controlled by the kinetic and thermodynamic factors in the second step the structure of the oxirane formed is decided by the reversibility of the aldolization and the reaction rate of the ring-closure. 

In the absence of other factors that may affect the stereochemical course of a reaction, the intermediacy of planar species is implicated by complete racemization of an optically active reactant during the substitution process. However, if the substitution occurs to some extent from one of the ion-pair species, then the nucleophile will react in an asymmetric environment and the product will not be racemic. This accounts for the observation that many dissociative reactions at stereogenic carbon centres do not produce racemic products (Ogg and Polanyi, 1935 Hammett, 1940 Cram and Haberfield, 1961). It is expected that this should also be the case in substitution at phosphorus. 

Three-co-ordinate sulphur. The most inorganic example has been the study of the kinetics and mechanism of hydrolysis of dithionites. Kinetics of attack of iodide and of thiourea at the 55 -dimethylsulphinium cation (M62S-NH2+) in water and in aqueous dimethyl sulphoxide indicate pre-equilibrium protonation followed by a rate-determining associative process. The overall activation entropy is negative. Nucleophilic substitution, by vinyl-lithium, at the triphenylsulphonium cation (PhaS ) is also associative. Indeed the species (30) is an intermediate rather than a transition state. Comparison of the stereochemical courses of reactions at tetrahedral phosphorus and at three-co-ordinate sulphur, which is... 

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

Experiments in which nucleophilic substitution takes place at a chiral center provide us with information about the stereochemical course of the reaction. One of the compounds studied to determine the stereochemistry of an S l reaction utilized the following chloroalkane. When either enantiomer of this molecule undergoes nucleophilic substitution by an S l pathway, the product is racemic. The reason is that ionization of this secondary chloride forms an achiral carbocation. Attack of the nucleophile can occur from either side of the planar carbocation carbon, resulting... 

The use of substituted vinyloxiranes shows that electronic and steric effects can strongly influence the reaction. Inter- or intramolecular reactions, acyclic or cyclic precursors, and apphcations to the synthesis of natural molecules will be presented in this section. We will analyze some general aspects of the reactivity of these electrophiles and focus on the regio- and stereochemical course of this reaction. The influence of the nucleophiles will be discussed, and finally, the overall potential of this Pd-catalyzed alkylation will be shown through some applications to the synthesis of cyclic molecules. 

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