Sn2 substitution reaction

While the fundamental mechanistic components of organic chemistry can be combined to describe complex mechanisms associated with complex reactions, the individual mechanistic components fall into a relatively small and well-defined group of four. These are SN1, SN2, El, and E2 reactions. In this chapter, the fundamentals associated with Sn2 reactions are presented. 

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Nucleophilic displacement reactions One of the most common reactions in organic synthesis is the nucleophilic displacement reaction. The first attempt at a nucleophilic substitution reaction in a molten salt was carried out by Ford and co-workers [47, 48, 49]. FFere, the rates of reaction between halide ion (in the form of its tri-ethylammonium salt) and methyl tosylate in the molten salt triethylhexylammoni-um triethylhexylborate were studied (Scheme 5.1-20) and compared with similar reactions in dimethylformamide (DMF) and methanol. The reaction rates in the molten salt appeared to be intermediate in rate between methanol and DMF (a dipolar aprotic solvent loiown to accelerate Sn2 substitution reactions). 

Organomagnesium and organolithium compounds are strongly basic and nucleophilic. Despite their potential to react as nucleophiles in SN2 substitution reactions, this reaction is of limited utility in synthesis. One limitation on alkylation reactions is competition from electron transfer processes, which can lead to radical reactions. Methyl and other primary iodides usually give the best results in alkylation reactions. 

Secondary bromides and tosylates react with inversion of stereochemistry, as in the classical SN2 substitution reaction.24 Alkyl iodides, however, lead to racemized product. Aryl and alkenyl halides are reactive, even though the direct displacement mechanism is not feasible. For these halides, the overall mechanism probably consists of two steps an oxidative addition to the metal, after which the oxidation state of the copper is +3, followed by combination of two of the groups from the copper. This process, which is very common for transition metal intermediates, is called reductive elimination. The [R 2Cu] species is linear and the oxidative addition takes place perpendicular to this moiety, generating a T-shaped structure. The reductive elimination occurs between adjacent R and R groups, accounting for the absence of R — R coupling product. 

Supercritical water (SCW) presents a unique combination of aqueous and non-aqueous character, thus being able to replace an organic solvent in certain kinds of chemical synthesis. In order to allow for a better understanding of the particular properties of SCW and of its influence on the rate of chemical reactions, molecular dynamics computer simulations were used to determine the free energy of the SN2 substitution reaction of Cl- and CH3C1 in SCW as a function of the reaction coordinate [216]. The free energy surface of this reaction was compared with that for the gas-phase and ambient water (AW) [248], In the gas phase, an ion-dipole complex and a symmetric transition... 

In the area of allenic non-natural product chemistry, the synthesis of the [34]alle-nophane 14 (Scheme 2.4) is particularly noteworthy, with all four of its allenic bridges being formed through subsequent SN2 substitution reactions of propargylic acetates with a methyl magnesium cuprate [14] (see Section 2.5 for an alternative synthesis of macrocyclic allenes). 

Furthermore, the copper-mediated SN2 substitution reaction is not restricted to carbon-carbon bond formation, as can be seen form the synthesis of silylallenes [15], stannylallenes [16] and bromoallenes [17] using propargylic electrophiles and the corresponding heterocuprates. The resulting allenes are often used as intermediates in target-oriented synthesis, e.g. in cyclization and reduction reactions [15-17]. 

The related zinc cuprates formed from diorganozinc reagents and copper(I) cyanide also undergo smooth SN2 substitution reactions with propargyl oxiranes in the presence of phosphines or phosphites (Scheme 2.12). These transformations can also be performed with catalytic amounts of the copper salt since no direct reaction between the organozinc reagent and the substrate interferes [31, 34], and therefore should also be applicable to functionalized organozinc compounds. 

As was the case for allene synthesis by copper-promoted Sn2 substitution reactions, the corresponding 1,6-addition to acceptor-substituted enynes has found sev-... 

A propargyl substrate having a substituent at the propargyl position is centrally chiral and an allenic product from the SN2 substitution reaction will be axially chiral. Chirality transfer in the SN2 reaction, accordingly, may be achieved starting from an enantiomerically enriched propargyl electrophile [29]. The reactions in Scheme 3.11 are some recent examples of the center to axis chirality transfer by Pd-catalyzed SN2 reactions [41, 42]. 

In most allylation reactions, only a catalytic amount of CuCN-2LiCl is required [41]. Use of the chiral ferrocenylamine 104 as a catalyst makes enables asymmetric allylation of diorganozinc reagents to be effected with allylic chlorides (Scheme 2.36) [78]. Related electrophiles such as propargylic bromides [79] and unsaturated epoxides [80] also undergo SN2 -substitution reactions (Scheme 2.37). 

Sn2 substitution reactions of alkyl halides with hard nucleophiles such as alkyl anions can be achieved most readily with the aid of organocopper chemistry [95]. Sn2 reactions with epoxides and aziridines are also synthetically useful [96]. The... 

The situation would, of course, be far worse for secondary isotope effects. For example, if we were to take 1.22 as the limiting 2° isotope effect for a SnI substitution reaction and 1.06 as the largest secondary isotope effect for a Sn2 substitution reaction, then we could ask what value of Kh/Icih would yield a value of... 

In the presence of solvent alone, the lifetime of the intermediate of the stepwise reaction of X-l-Y in the narrow borderline between the S l and Sn2 substitution reactions of azide ion (—0.32 < a" " < —0.08, Fig. 2.2) is 1/ = 10 ° s. Azide ion is 10°-10 -fold more reactive than water toward triarylmethyl carboca-tions and related electrophiles, and this selectivity is independent of carbocation reactivity, so long as the reactions of both azide ion and solvent are limited by... 

Sn2 Reactions. Given its central role in the development of modem physical organic chemistry, it is no surprise that the Sn2 substitution reaction is the most widely studied of all gas-phase anionic processes. In a classic study, Ohn-... 

Facile SN2 substitution reactions of halogens are expected from the electron-attracting characteristics of the neighboring carbonyl function, which should make the transition state for attack by a nucleophilic reagent more favorable ... 

A similar picture holds for other nucleophiles. As a consequence, there might seem little hope for a nucleophile-based reactivity relationship. Indeed this has been implicitly recognized in the popularity of Pearson s concept of hard and soft acids and bases, which provides a qualitative rationalization of, for example, the similar orders of reactivities of halide ions as both nucleophiles and leaving groups in (Sn2) substitution reactions, without attempting a quantitative analysis. Surprisingly, however, despite the failure of rate-equilibrium relationships, correlations between reactivities of nucleophiles, that is, comparisons of rates of reactions for one carbocation with those of another, are strikingly successful. In other words, correlations exist between rate constants and rate constants where correlations between rate and equilibrium constants fail. 

The phosphate-adduct radical is also formed, when the reaction is initiated by S04 [reaction (18)] in the presence of phosphate ions (Behrens et al. 1988). This may either be due to an Sn2 substitution reaction [reaction (19)] or a reaction of the phosphate ion with the radical cation [reaction (17)] formed either by an elimination of S042- plus H+ [reaction (20)] and subsequent protonation of the N(3)-centered radical [equilibrium (22)] or by S042- elimination [reaction (21)], as envisaged originally. The reaction of the radical cation with phosphate would then give rise to the observed radical [reaction (23)]. 

An example of an SN2 substitution reaction with a mixed zinc-copper reagent is shown in Scheme 22.22. The product 9 was used to prepare the bicyclic enone 10. In this example the starting alcohol gave rise to the asymmetric induction. The substitution was anti-selective.152... 

The considerations given above imply that reactions of nucleophiles with carbonyl centres may be described on the basis of either a double potential well model as advanced for SN2 substitution reactions (cf. Fig. 4) or a triple potential well model depending on whether the tetrahedral structure corresponds to a potential maximum or minimum, respectively. 

Elimination reactions are facile processes as far as they have been studied in the gas phase. It is, however, often difficult to distinguish them from SN2 substitution reactions since both reactions mostly lead to the same product ions, but not to the same neutral products which in most experiments are not known (Smith et al., 1980 Jones et al., 1985). In that respect the reactions of cyclic compounds, such as cyclic ethers, are good probes for the study of elimination reactions because the leaving group remains with the anion. For example, the reaction of NH2 with tetrahydrofuran leads to (M — H) ions. Deuterium labelling has shown that the proton is abstracted exclusively from the P-position (DePuy and Bierbaum, 1981b DePuy et al., 1982b). 

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