On Sn2 reactivity

A similar analysis suggests the absence of significant negative charge development as well. The fact that p-haloethyl derivatives have only a weak deactivating effect, rather than an activating effect on SN2 reactivity (Hine and Brader, 1953 Hine, 1962 Streitwieser, 1962) implies that there is no... 

Fig. 2.9. Steric effects on Sn2 reactivity substituent compression in the transition state.

Fig. 2.10. Electronic effects on Sn2 reactivity conjugative stabilization of the transition state by suitably aligned unsaturated substituents.

Other measures of nucleophilicity have been proposed. Brauman et al. studied Sn2 reactions in the gas phase and applied Marcus theory to obtain the intrinsic barriers of identity reactions. These quantities were interpreted as intrinsic nucleo-philicities. Streitwieser has shown that the reactivity of anionic nucleophiles toward methyl iodide in dimethylformamide (DMF) is correlated with the overall heat of reaction in the gas phase he concludes that bond strength and electron affinity are the important factors controlling nucleophilicity. The dominant role of the solvent in controlling nucleophilicity was shown by Parker, who found solvent effects on nucleophilic reactivity of many orders of magnitude. For example, most anions are more nucleophilic in DMF than in methanol by factors as large as 10, because they are less effectively shielded by solvation in the aprotic solvent. Liotta et al. have measured rates of substitution by anionic nucleophiles in acetonitrile solution containing a crown ether, which forms an inclusion complex with the cation (K ) of the nucleophile. These rates correlate with gas phase rates of the same nucleophiles, which, in this crown ether-acetonitrile system, are considered to be naked anions. The solvation of anionic nucleophiles is treated in Section 8.3. 

Organic solvents such as benzene, ether, and chloroform are neither protic nor strongly polar. What effect would you expect these solvents to have on the reactivity of a nucleophile in SN2 reactions ... 

As pyramidal amides5,32 their Sn2 reactivity with neutral nucleophiles like /V-methylaniline parallels that of a-haloketones with amines, which, as described in an earlier section, are also strongly affected by steric effects on the a -carbon.183 SN2 reactions are in general strongly and adversely influenced by steric effects and branching / to the reactive centre and the same appears to be true for /V-acyloxy-/V-alkoxyamides 30b and 29a-e. Broadly speaking, their mutagenic activity is affected similarly. 

The effect of the 1,2,5-thiadiazole system on the reactions of carbon-bound substituents can be summarized as follows (i) stabilization of carbanions (ii) destabilization of carbenium ions (iii) enhanced Sn2 reactivity and repressed SnI reactivity <68AHC(9)107>. Aryl substituents are rendered more reactive to nucleophiles <72US(A)25> and deactivated in reactions with electrophiles, which are directed to the orthojpara positions by the thiadiazole ring <72IJS(A)25,78MI409-01>. 

The main advantage of the VTST method is that it can be applied also to realistic simulations of reactions in condensed phases.The optimal planar coordinate is determined by the matrix of the thermally averaged second derivatives of the potential at the barrier top. VTST has been applied to various models of the CP-i-CHsCl Sn2 exchange reaction in water, a system which was previously studied extensively by Wilson, Hynes and coworkers.Excellent agreement was found between the VTST predictions for the rate constant and the numerically exact results based on the reactive flux method. The VTST method also allows one to determine the dynamical source of the friction and its range, since it identifies a collective mode which has varying contributions from differ-... 

Substituent effects Carbocations are formed in the S l reactions. The more stable the carbocation, the faster it is formed. Thus, the rate depends on carbocation stability, since alkyl groups are known to stabilize carbocations through inductive effects and hyperconjugation (see Section 5.2.1). The reactivities of SnI reachons decrease in the order of 3° carbocation > 2° carbocation > 1° carbocation > methyl cation. Primary carbocation and methyl cation are so unstable that primary alkyl halide and methyl halide do not undergo SnI reachons. This is the opposite of Sn2 reactivity. 

A quantitative assessment of the effects of head group bulk on Sn2 and E2 reactions in cationic micelles has been made.148 The kinetics of the acid-catalysed hydrolysis of methyl acetate in the presence of cationic, anionic, and non-ionic surfactants has been reported on.149 The alkaline hydrolysis of -butyl acetate with cetyltrimethylammonium bromide has also been investigated.150 The alkaline hydrolysis of aromatic and aliphatic ethyl esters in anionic and non-ionic surfactants has been studied.151 Specific salting-in effects that lead to striking substrate selectivity were observed for the hydrolysis of />-nitrophenyl alkanoates (185 n = 2-16) catalysed by the 4-(dialkylamino)pyridine-functionalized polymer (186) in aqueous Tris buffer solution at pH 8 and 30 °C. The formation of a reactive catalyst-substrate complex, (185)-(186), seems to be promoted by the presence of tris(hydroxymethyl)methylammonium ion.152... 

Hine, J. Thomas, C. H. Ehrenson, S. J. The effect of halogen atoms on the reactivity of other halogen atoms in the same molecule. V. The Sn2 reactivity of methylene halides. 

Investigation of the reaction of 3,3-disubstituted 1,2-dioxetanes with various heteroatom nucleophiles establishes the SN2 reactivity of these strained peroxides [134]. As reported in Sch. 80 for dioxetane 141, the sterically exposed oxygen of the peroxide bond becomes the site of nucleophilic attack to produce an anionic or zwitterionic adduct 142. Different reaction channels become available for the intermediate which depend on the chemical nature of the nucleophile. So epoxy alcohol 143, p-hydroxy hydroxylamine 144, diol 145, cyclic carbonate 146, and cyclic sulfite 147 can be obtained (Sch. 80) [134],... 

To alkylate unsymmetrical ketones on less substituted side LDA - kinetic lithium enolate with SN2-reactive electrophiles... 

It is beyond the scope of this chapter to review the numerous attempts to model Sn2 reactivity. Besides models describing the reaction qualitatively in terms of valence bond configurations and mostly aiming at interpreting substituent effects, anomalous Bronsted slopes and appearance of intermediates on the reaction pathway (see Pross, 1985 Shaik, 1985, and references therein), essentially two types of quantitative treatments have been developed. The more rigorous one, based on ab initio quantum chemical calculations (Berthier et al., 1969 Jorgensen, 1988) has reached quantitative... 

Cyclopentene oxide is very unreactive (k < l( itcyclohexene oxide), an observation clearly not in accord with expected Sn2 reactivity it gives cyclopentanone as the only observed product. This ketone cannot be formed by antiperiplanar hydride displacement of bromide from the tra/is-bromohydrin, whereas the c/5-bromohydrin could easily adopt the necessary conformation for hydride migration. Almost certainly the latter is formed by slow, perhaps rate-determining 5n2 attack by bromide on the initially formed trans-bromohydrin salt, as outlined in equation (121). This secondary reaction may be more important with Lil than with LiBr, although this has not been proven (see also equation 83 and discussion of MgX2-catalyzed reactions). 

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