Steric effects in Sn2 reactions

There are very large differences in the rates at which the various kinds of alkyl halides— methyl, primary, secondary, or tertiary—nndergo nncleophilic snbstitntion. As Table 8.2 shows for the reaction of a series of alkyl bromides  

In general, Sn2 reactions exhibit the following dependence of rate on substrate structure  

Reactivity of Some Alkyl Bromides Toward Substitution by the Sn2 Mechanism  

Alkyl bromide Structure Class Relative rate  

Least crowded-most reactive Most crowded-least reactive 

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One of the early applications of TS modelling was the work on steric effects in Sn2 reactions by DeTar and co-workers, and it has more recently been advocated by Houk... 

Besides these rate-reducing steric substituent effects, in SN2 reactions there is a rate-increasing electronic substituent effect. It is due to facilitation of the rehybridization... 

Two energy diagrams depicting the effect of steric hindrance in Sn2 reactions... 

If the potential leaving group is attached to unsaturated carbon, as in vinyl chloride or phenyl chloride, attack by nucleophiles is also extremely difficult, and these compounds are very unreactive in Sn2 reactions compared with simple alkyl halides. In these cases, the reason is not so much steric but electrostatic, in that the nucleophile is repelled by the electrons of the unsaturated system. In addition, since the halide is attached to carbon through an 5p -hybridized bond, the electrons in the bond are considerably closer to carbon than in an 5/ -hybridized bond of an alkyl halide (see Section 2.6.2). Lastly, resonance stabilization in the halide gives some double bond character to the C-Hal bond. This effectively strengthens the bond and makes it harder to break. This lack of reactivity is also tme for SnI reactions (see Section 6.2). 

Keep in mind when filling in the E2 chart, that you don t have the same steric concerns in tertiary substrates that you had in SN2 reactions. The base does not need to get in and attack the carbon. It only has to pull off a proton. Sterics is no longer an effect in this case, and you can have E2 reactions on tertiary substrates ... 

As a second example, we have determined the influence of solvation on the steric retardation of SN2 reactions of chloride with ethyl and neopentyl chlorides in water, which has recently been studied by Vayner and coworkers [91]. In their study solvent effects were examined by means of QM-MM Monte Carlo simulations as well as with the CPCM model. Solvation causes a large increase in the activation energies of these reactions, but has a very small differential effect on the ethyl and neopentyl substrates. Nevertheless, a quantitative difference was found between the stability of the transition states determined using discrete and continuum treatments of solvation, since the activation free energies for ethyl chloride and neopentyl chloride amount to 23.9 and 30.4kcalmoF1 according to MC-FEP simulations, but to 38.4 and 47.6 kcal moF1 from CPCM computations. 

Correlation of nucleophilic rate data for phenyldimethylsulfonium ions with common nucleophiles, with pXj values shows that the slopes of the lines, correlate qualitatively with the Edwards hardness parameter for the nucleophile and not with the Swain-Scott n parameter. " " d5,d5-2,4,6-Trimethyl-l,3,5-triammocyclohexane is weakly basic in aqueous solution, because of steric inhibition to solvation of the conjugate acid. " The three NH2 groups are axial and the steric effect also results in reduced reactivity as a nucleophile in Sn2 reactions. Highly stereoselective syntheses of P-C-, N-, and O-glycosides have been carried out by addition of anionic nucleophiles to glycosyl iodides. " 5n2 reactions are involved, but some substrates are susceptible to E2 elimination when treated with highly basic anions. 

In cases where steric factors are kept constant, electronic effects on Sn2 reactions can be observed however, these effects are found to be comparatively mail. Some 8 2 reactions are speeded up slightly by electron release, and others are speeded up slightly by electron withdrawal, but it is not usually possible to predict which will be the case simply from the structures involved... 

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