Nucleophilicity solvation effects

The remarkable enhancement of anion nucleophilicity in Sn2 reactions carried out in dipolar aprotic solvents is a solvation effect.Solvents like DMF and DMSO are very polar owing to the charge separation indicated in 1 and 2. 

There are two other approaches to enhancing reactivity in nucleophilic substitutions by exploiting solvation effects on reactivity the use of crown ethers as catalysts and the utilization of phase transfer conditions. The crown ethers are a family of cyclic polyethers, three examples of which are shown below. 

Fig. 9 Comparison of polar and steric effects of alkyl groups on bromination rates of linear ( ), branched (O) and adamantyl (A) alkenes in acetic acid and in methanol (Ruasse and Zhang, 1984 Ruasse et al., 1990). Polar effects are identical in both solvents [full line, eq. (24)], but steric effects differ. Deviations of branched alkenes are attributed to steric inhibition of nucleophilic solvation by methanol.

Rate constants and products have been reported for solvolysis of benzhydryl chloride and /7-methoxybenzyl chloride in 2,2,2-trifluoroethanol (TFE)-water and-ethanol, along with additional kinetic data for solvolysis of r-butyl and other alkyl halides in 97% TFE and 97% hexafluoropropan-2-ol. The results are discussed in terms of solvent ionizing power Y and nucleophilicity N, and contributions from other solvation effects are considered. Comparisons with other 3 nI reactions show that the solvolyses of benzhydryl chloride in TFE mixtures are unexpectedly fast an additional solvation effect influences solvolysis leading to delocalized cations. 

The most common deviation is the exceptionally high reactivity of nucleophiles, such as hydroperoxide, hypochlorite and hydroxamate ions, with atoms bearing lone-pair electrons next to the nucleophilic centre. This phenomenon, known as the alpha-effect287, is found for aminolysis reactions of esters also285, and is commonly observed for attack at electrophilic centres where reactivity depends fairly strongly on the basicity of the nucleophile. Negative deviations may be evidence of steric hindrance, or in a few cases, in particular that of hydroxide ion, may reflect special solvation effects on the pKa or the nucleophilicity (or both) of the nucleophile. 

However, reaction of the 4-aryl-1,3-dithiolylium salts (48) with 2 moles of potassium O-ethyl dithiocarbonate in acetone produces the thioether (49) instead of the expected adduct, a result which has been explained in terms of the different solvation effect of the nucleophile in acetone and acetonitrile (77JOC1543). The reaction is reversed by treatment of (49) with perchloric acid. 

Perhaps the most spectacular success of explanations based on solvation of ground states, published to date, is the dissection of activation parameters for solvolysis of t-butyl chloride in mixtures of ethanol and water, first discussed by Winstein and Fainberg (1957). The complex variation of AH and AS (Fig. 21) has been shown to be due almost entirely to ground state solvation effects, at least for the solvents ethanol—40% ethanol/water studied by Arnett et al. (1965). For 90%, 80%, 70%, 60%, 50% and 40% ethanol/water the parameter AH1 for solvation of the transition state (by transfer from the gas phase) was calculated to be linearly proportional to the corresponding value of AS, as expected from the behaviour of simple salts. The point for pure ethanol did not fall on the calculated line, and this was attributed to nucleophilic solvent assistance. The variation in AG, AH and AS (Fig. 21) can be reproduced remarkably well using ethane and the zwitterionic a-amino acid, glycine, as model compounds (Abraham et al., 1975 see also Abraham, 1974 Abraham and Abraham, 1974). 

An experimental Acan be derived from the temperature dependence of the second-order rate constant, which yielded a value of 25.9 kcal/mol.59 Although it appears that this disagrees with the computed free energy of activation (16.6 kcal/ mol) for the reaction of H3N + CH3SH2 in water, the difference actually originates from the intrinsic reactivity of the two reactions. The additional methyl group substitutions both on the nucleophile and substrate raise the gas-phase barrier by 10 kcal/mol to a value of 10.5 kcal/mol at the HF/6-31G(d) level. Taking the methyl substitution effect into account, the computed solvation effect in fact is in accord with experiment,59 which is about 15 kcal/mol (25.9 — 10.5 kcal/mol). 

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