The Stereochemistry of an SN2 Reaction

The reaction of (R)-(-)-2-bromooctane with hydroxide is an 5 2 reaction and takes place with complete inversion of configuration  

Sn2 reactions that involve breaking a bond to a chirality center can be used to relate configurations of molecules because the stereochemistry of the reaction is known. 

9 The Reaction of tert-Butyl Chloride with Hydroxide Ion  

Let us now consider another mechanism for nucleophilic substitution the SnI reaction. When tert-butyl chloride reacts with sodium hydroxide in a mixture of water and acetone, the kinetic results are quite different than for the reaction of chloromethane with hydroxide. The rate of formation of tert-butyl alcohol is dependent on the concentration of tert-butyl chloride, but it is independent of the concentration of hydroxide ion. Doubling the tert-butyl chloride concentration doubles the rate of the substitution reaction, but changing the hydroxide ion concentta-tion (within limits) has no appreciable effect tert-Butyl chloride reacts by substitution at virtually the same rate in pure water (where the hydroxide ion is 10 M) as it does in 0.05M aqueous sodium hydroxide (where the hydroxide ion concentration is 500,000 times larger). (We shall see in Section 6.10 that the important nucleophile in this reaction is a molecule of water.) 

the rate equation for this substitution reaction is first order with respect to tert-butyl chloride and first order overall  

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In summary, there are two principal factors which determine the stereochemistry of an Sn2 reaction ... 

Stereochemistry of the Sn2 reaction A nucleophile donates its electron pairs to the C—X bond on the backside of the leaving group, since the leaving group itself blocks attack from any other direction. Inversion of stereochemistry is observed in the product of an Sn2 reaction. The reaction is stereospecific since a certain stereoisomer reacts to give one specific stereoisomer as product. 

This chapter covers reactions where a stereogenic sp3 center is inverted or undergoes a substitution reaction. To control the stereochemical outcome of a substitution reaction, an SN2 mechanism usually has to be used. As a consequence, inversion of configuration is usually observed, although in some reactions two sequential substitutions can occur to give the overall appearance of retention. The use of an SN2 reaction necessitates the establishment of the stereogenic center in the reactant. When an isolated center undergoes this type of reaction, it is usually to correct stereochemistry. 

To distinguish between SN1 and SN2 mechanisms of solvolysis requires other criteria, notably stereochemistry (Sections 8-5 and 8-6), and the elfect of added nucleophiles on the rate and nature of the reaction products. For example, it often is possible to distinguish between SN1 and SN2 solvolysis by adding to the reaction mixture a relatively small concentration of a substance that is expected to be a more powerful nucleophile than the solvent. If the reaction is strictly SN1, the rate at which RX disappears should remain essentially unchanged because it reacts only as fast as R forms, and the rate of this step is not changed by addition of the nucleophile, even if the nucleophile reacts with R . However, if the reaction is SN2, the rate of disappearance of RX should increase because RX reacts with the nucleophile in an SN2 reaction and now the rate depends on both the nature and the concentration of the nucleophile. (See Exercises 8-5 and 8-6.)... 

Mg2+ is associated with a large number of enzymes involving the hydrolysis and transfer of phosphates. The MgATP complex serves as the substrate in many cases. As noted in Section 62.1.2.2.2, the interaction of Mg2+ with the ATP enhances the transfer (to a substrate or water) of the terminal phosphoryl group. The results of many studies with model compounds lead to the postulate of an SN2 mechanism for this reaction.125 Associative pathways allow greater control of the stereochemistry of the substitution, and the rates of such processes are accelerated more effectively by metal ions. 

Thomson I. Click Organic Process to view an animation showing the stereochemistry of the Sn2 reaction. 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

Another problem with the reaction of phenols with aziridines is the selectivity between O-alkylation vs C-alkylation. A recent report has identified that the use of (ArO)3B selects for C-alkylation <06OL2627>. Most of the examples reported in this paper showed less than 5% of the O-alkylation product. What is interesting about this report is the stereochemistry of the product. While the mechanism is not known, the product is formally an SNl type product. Generally less than 5% was the product of inversion of configuration (the Sn2 product). In addition to the A-tosyl, both the A-Cbz and A-Dpp aziridines gave excellent yields of aziridine-opened product. 

Step 1 is fundamentally an SN2 reaction (kinetics related to structural variations of the reactants,16 8 retention of stereochemistry at phosphorus912), except in those instances wherein a particularly stable carbocation is produced from the haloalkane component.13 A critical experiment concerned with verification of the Sn2 character of Step 1 by inversion of configuration at the carbon from which the leaving group is displaced was inconclusive because elimination rather than substitution occurred with the chiral secondary haloalkane used.14 An alternative experiment suggested by us in our prior review using a chiral primary substrate apparently has not yet been performed.2... 

Single Electron Transfer A single electron transfer (SET) mechanism is often difficult to distinguish from an SN2 reaction because the principal product of these two pathways is the same, apart from the stereochemistry at carbon (race-mization instead of inversion). The radicals formed can recombine rapidly in a solvent cage (inner-sphere ET) [2, 193, 194]. The [HFe(CO)5] -catalyzed deiodina-tion of iodobenzene may serve as an example [179] (Eq. (13)). 

The oxidative addition of alkyl halides can proceed in different ways, although the result is usually atrans addition independent of the mechanism. In certain cases the reaction proceeds as an SN2 reaction as in organic chemistry. That is to say that the electron-rich metal nucleophile attacks the carbon atom of the alkyl halide, the halide being the leaving group. This process leads to inversion of the stereochemistry of the carbon atom (only when the carbon atom is asymmetric can this be observed). There are also examples in which racemisation occurs. This has been explained on the basis of a radical chain... 

A similar reaction pathway was found for the Sn2 substitution of an epoxide with a lithium cuprate cluster [124]. In contrast to that in the MeBr reaction, the stereochemistry of the electrophilic carbon center is already inverted in the transition state, providing the reason for the preferred trans-diaxial epoxide-opening widely observed in synthetic studies. The TS for the Sn2 reaction of cyclohexene oxide is shown in Eq. 10.12. 

An important question regarding SN2 reactions in the gas phase concerns the stereochemistry and the extent to which a Walden inversion occurs at the reaction site. Since the experimental techniques monitor exclusively ion concentration, the actual nature of the neutrals produced in the reaction is subject to some doubt. An indirect method to ascertain the nature of the products is to assess the thermochemistry of other possible reaction channels. In the case of methyl derivatives, the alternatives are few and result in highly endothermic reactions, as exemplified in (22) and (23). For more complicated systems, this argument may not be satisfactory or may not yield an unequivocal answer. 

Acidic conditions also can be used for the cleavage of oxacyclopropane rings. An oxonium ion is formed first, which subsequently is attacked by the nucleophile in an SN2 displacement or forms a carbocation in an SN1 reaction. Evidence for the SN2 mechanism, which produces inversion, comes not only from the stereochemistry but also from the fact that the rate is dependent on the concentration of the nucleophile. An example is ring opening with hydrogen... 

As a consequence of this stereoelectronic requirement, the opening of a symmetrical epoxide (61 by a nucleophile gives a product of defined stereochemistry (cf. J). The same requirement necessarily holds for the reverse process, i, e. 7 6. Indeed, the formation of an epoxide from 7 can be regarded as an internal SN2 reaction (footnote 20 in ref. 4, see also 5). 

Stereoelectronic effects can also be considered in the SN2 1 reaction. An excellent review on this topic has been published recently by Magid (23). Although there is still some discussion concerning the concertedness of this reaction, as pointed out by Magid, the stereochemistry of the process... 

The only apparent difference between the two mechanisms is the stereochemistry of the product. If the reaction proceeds through an Sn2 mechanism, it gives inversion of configuration conversion of an R starting material into an S product, or vice versa. If the reaction proceeds through a carbocation intermediate via an SN1 mechanism, we get a racemic mixture. 

It turns out that it is difficult to use the ketone to control the stereochemistry of the epoxidation. If acrylic acid is used as the dienophile, bromolactonisation of the product 67 gives a mixture of five- 68 and six-membered 69 lactones in 86% yield and a 1 1.5 ratio. Fortunately, treatment of both with an alkyl-lithium makes the same epoxide 70 by ring opening and Sn2 closure of the epoxide.8 The reaction works well only with an electron-withdrawing group X such as SPh that must be removed later. Addition of MeLi to the ketone and elimination gives 62. 

Additives, in some cases, are used to modulate the stereochemistry of glycosylation by directly participating in the reaction process. Raymond Lemieux and coworkers, for example, demonstrated that a-pyranosyl bromides would transform into the P-pyranosyl bromides in situ in the presence of tetraalkylammonium bromide [7], The more reactive p-pyranosyl bromides would react with glycosyl acceptors in an SN2-type manner to give the kinetically controlled a-linked glycosides. 

Designing an experiment to demonstrate that an SN2 reaction occurs with inversion of configuration is not as simple as it might appear at first glance. For example, consider using the reaction of 2-chlorobutane with hydroxide ion to produce 2-butanol to determine the stereochemistry of the SN2 reaction ... 

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