SN2 -type reaction

It Is not easy to design an experiment to test the subtle stereochemical requirement of the transition state of a reaction. One experimental approach is to attach the nucleophile to the substrate, creating a situation where this nucleophile can undergo two different competing reactions. In many cases, the nucleophile can more easily fulfill the stereochemical requirement of one process and only one reaction is observed. The experiment is almost perfectly designed when the process which takes place is stereoelec-tronically allowed and leads to the kinetic rather than the thermodynamic product, or when the process which does not take place is not stereoelec-tronlcally allowed but is otherwise favored on the basis of steric arguments or entropy consideration, especially when that would have led to the thermodynamic product. 

As a consequence of this stereoelectronic requirement, the opening of a Symmetrical epoxide ) by a nucleophile gives a product of defined stereochemistry (cf. 2 The same requirement necessarily holds for the reverse process, the formation of an epoxide from can be regarded as an internal SN2 reaction (footnote 20 in ref. 4, see also 5). 

In the case of an unsymmetrical epoxide which is conformationally rigid such as 8, two different products are theoretically possible, the diequato-rial product 10 resulting from the attack at C-2 or the diaxial product 1 from the attack at C-3. 

Most addition reactions of electrophilic reagents to double-bonds which are known to proceed through an epoxide-like intermediate (i.e. the three-membered ring intermediate J4), and, therefore, must follow the same principle, yielding the trans-diaxial product J5 (7). 

This is true for the addition of hydrogen halide (H-X), halogens (X-X) and other electrophilic reagents (NO-Cl, I - N3, etc.) to cyclohexenes. The oxymercuration reaction (Hg(0Ac)2 in the presence of several nucleophiles (H2O. AcOH, ROH) is another well known example. 

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The unique chemical behavior of KO2 is a result of its dual character as a radical anion and a strong oxidizing agent (68). The reactivity and solubiHty of KO2 is gready enhanced by a crown ether (69). Its usefiilness in furnishing oxygen anions is demonstrated by its appHcations in SN2-type reactions to displace methanesulfonate and bromine groups (70,71), the oxidation of benzyHc methylene compounds to ketones (72), and the syntheses of a-hydroxyketones from ketones (73). 

Because the new carbon-carbon bond is formed by an SN2-type reaction the alkyl halide must not be sterically hindered. Methyl and primary alkyl halides work best secondary alkyl halides give lower yields. Tertiary alkyl halides fail, reacting only by elimination, not substitution. 

Here (in contrast to the approach taken in Chapter 2) we do not assume that the energy of each valence bond structure is correlated with its solvation-free energy. Instead we use the actual ground-state potential surface to calculate the ground-state free energy. To see how this is actually done let s consider as a test case an SN2 type reaction which can be written as... 

The von Braun reaction (Scheme 6) is another basic reaction for C—N bond cleavage 32). Tetrahydroberberine (26) was heated under reflux with cyanogen bromide in benzene to afford the bromocyanide (28) and the unsaturated cyanide (29) through C-6—N and C-14—N bond cleavage, respectively. The C-8—N bond cleavage product was not obtained because of the steric hindrance of the methoxyl group at C-9 in SN2-type reactions 33). The... 

Similar treatment explains the prevalence of the syw-mode 147>148) in a,y-interaction in Sn2 reactions (Fig. 7.37a). The a,5-interaction (e.g. Sn2 type reaction) is predicted to occur with syw-mode, and a,e-interac-tion with anti-mode (Fig. 7.37b and c). 

A phosphotriesterase isolated from the soil bacterium Pseudomonas diminuta is the best characterized enzyme of this type. There is evidence for the presence of two active site Zn2+ ions in vivo. A crystal structure of the dinuclear Cd2+ form is available in which the metal ions are bridged by a carbamylated Lys-amino group with a metal-metal distance of 3.8 A [ 18]. Substrate hydrolysis follows a SN2 type reaction and nucleophilic attack of M-OH is likely, but mechanistic details are not yet clear. 

Not only is the leaving group important, but if the reaction has SnI character, the stability of the positive charge left behind is also important. In the examples above, a primary carbocation is difficult to form and therefore the reaction of busulfan with glutathione would likely be a SN2-type reaction, whereas the nitrenium ion and carbocation formed from N -acetylaminofluorene and safrole, respectively, are relatively stable and likely to be Sn 1 -type reactions. 

A similar vinylic cation was once claimed to be formed during the solvolysis of cyclohexylidenemethyl triflate in aqueous methanol at 140 °C (eq 9),13 but this reaction could occur via participation and SN2-type reaction. Solvolysis of the optically active 4-methyl-substituted triflate under the same reaction conditions took place with complete retention of the optical purity.14... 

The use of the zinc-copper couple to effect the reduction of the methanesulfonate 168 with rearrangement furnished 169 (Scheme 20.34) [10]. Treatment of 168 with methylmagnesium bromide in the presence of copper(I) cyanide to induce an SN2 -type reaction produced the methylated adduct 170. The half-life of the Myers-Saito cyclization of 169 is 66 h at 37 °C, whereas that of 170 is 100 min. The faster rate of cyclization for 170 has been attributed to a steric effect favoring the requisite s-cis or twisted s-cis conformation. 

Protonation of the epoxide by AcOH is followed by nucleophilic ring-opening with Pd(0) (SN2-type reaction) to give an allylpalladium(II) complex. The AcO- then attacks the allyl ligand, regenerating Pd(0) and affording the product. 

The foregoing examples of differential reactivities of rotamers may be summarized by saying that the reactivity is controlled by the steric factor. The difference in the reactivities of rotamers of 9-(2-bromomethyl-6-methyl-phenyl)fluorene (56) in SN2 type reactions falls in the same category (176). However, the substituent effect is not limited to a steric one there can be conformation-dependent electronic effects of substituents as well. A pertinent example is found in the reactivity of the bromomethyl compound (56) when the rotamers are heated in a trifluoroacetic acid solution (Scheme 10). The ap form gives rise to a cyclized product, whereas the sp form remains intact (176). The former must be reacting by participation of the it system of the fluorene ring. 

Dunitz (180) has collected X-ray crystallographic data for carbonyl compounds that possess nucleophilic atoms in proximity to C=0, and has postulated that such molecules can be used as models for the incipient transition state (reaction coordinate) for the nucleophilic addition to carbonyl compounds. Atrop-isomeric compounds have the potential, by providing a variety of such data, for understanding the incipient transition states. For example, the interaction found in the 1,4-dimethoxy-9-(2-acyloxyethyl)triptycenes (130) can be viewed as a model for SN2 type reactions where the acyloxy group is the leaving group and the methoxy is the nucleophile. In an extreme case of this sort, cyclization actually takes place. Such an example has been reported (181). 

NH3 is generated above pH 4.7. In these reactions, the hydride complexes [(Cp Ir)2(p-H)(p-OH)(g-HCOO)]" (25) and [Cp Ir(bpy)(H)]" (31), which would be generated from the reactions of 24 and 28 with HCOO, would be key catalytic intermediates. The dehalogenation of the alkyl halides using 24 did not occur, most likely due to the bulkiness of the active catalyst 25 compared to 31 in SN2-type reactions (entry 5). 

The SN2-type reaction can be considered simply as being initiated by attack of a nucleophile onto the electron-deficient end of a polarized bond X-Y. 

Acid hydrolysis of an octahedral metal ion complex is typically a dissociative or SNl-type reaction. In the case of base hydrolysis, reactions tend to display SN2-type reaction mechanisms, although others take place by what is termed an SnI-conjugate base mechanism. The latter involves attack by an electrophile to abstract a proton... 

Simple kinetic measurements can, however, be an inadequate guide to which of the above two mechanisms, SN1 or S,v2, is actually operating in, for example, the hydrolysis of a halide. Thus, as we have seen (p. 45), where the solvent can act as a nucleophile (solvolysis), e.g. H20, we would expect for an SN2 type reaction,... 

Since the pioneering work of Karl Freudenberg on displacements of carbohydrate p-toluene-sulfonates [1-5], bimolecular nucleophilic substitutions became one of the most employed and useful reactions in carbohydrate chemistry. Indeed SN2-type reactions have allowed the introduction of a variety of heteroatoms (halogens, N-, O-, S-) into carbohydrates, and the resulting compounds have been used in many synthetic and biological contexts [6],... 

The Thil gene, which encodes aother sulfurtransferase protein, is also needed.3743 The enzymology of the insertion of this sulfur into the thiazole is uncertain but may resemble that involved in synthesis of biotin, lipoic acid, and molybdopterin.374 Linkage of the two parts of the thiamin molecule (step d, Fig. 25-21) is catalyzed by thiamin phosphate synthase, evidently via an SN2 type reaction.377-37713... 

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