Desolvation of nucleophiles

The value of = 1 X 10 s for the first-order rate constant for collapse of an ion pair between Me-4 and pentaflourobenzoate ion is larger than the second-order rate constant rcoo = 5x10 M s reported for the bimolecular addition of alkane carboxylates to Me-4. This second-order rate constant is limited by the rate constant for formation of an ion pair between Me-4 and a carboxylate ion. The larger barrier to encounter-limited reactions of carboxylate ions compared with the diffusion-limited reactions of anions such as azide ion, = 5 X 10 represents the barrier to desolvation of nucleophile that must precede formation of an ion pair between Me-4 and a carboxylate ion (Scheme 13). ... 

Substitutions of Sn2 type are frequently used for carbon-carbon or carbon-heteroatom bond formation. However, little attention has been devoted to the development of such reactions in water. This is likely due to concerns about competitive hydrolysis of the electrophile in water and SN2-type reactions being slower in aqueous conditions than in aprotic polar solvents due to the higher cost of desolvation of nucleophiles. We shall discuss the ring opening of epoxides and aziridines, palladium-catalyzed allylic substitutions, as well as acylations and sulfonylations of amines and alcohols. 

A qualitative difference in the type of solvation (not simply in the strength of solvation) in a series of nucleophiles may contribute to curvature. Jencks has examined this possibility. " " An example is the reaction of phenoxide, alkoxide, and hydroxide ions with p-nitrophenyl thiolacetate, the Br insted-type plot showing Pnuc = 0.68 for phenoxide ions (the weaker nucleophiles) and Pnu = 0.17 for alkoxide ions. It is suggested that the need for desolvation of the alkoxide ions prior to nucleophilic attack results in their decreased nucleophilicity relative to the phenoxide ions, which do not require this desolvation step. 

According to Jencks et al.,193 negative (3nuc values result from a combination of minimal progress of bond formation at the transition state and the requirement for partial desolvation of the nucleophile before it enters the transition state. In a first approximation (3nuc may be expressed by Equation (50) where [3d and (3nuc are defined by Equations (51) and (52), respectively. Kd represents... 

Calculations of reactions of simple nucleophiles such as H with carbonyl compounds show that, in the gas phase, there is no barrier. Activation energies in solution arise from desolvation of the nucleophile. However, reactions of a nucleophile with an alkene or an alkyne do have a barrier in the gas phase. 

Kinetic studies of the reaction at pH 7.7 of 4-nitrophenyl acetate with three hydroxa-mates, RCONHO- (R = Me, Ph, 2-HOC6H4) in various water-solvent (DMSO, DMF, MeCN, and 1,4-dioxane) mixtures have shown that these a-effect nucleophiles react faster with increasing percentages of DMF and DMSO, but not with MeCN and 1,4-dioxane. The likely explanation is desolvation of the hydroxamate ions by the highly polar solvents, DMF and DMSO.13... 

The reorganization of the solute about reacting species is not limited to catalytic complexes, however. Studies of nucleophilicity of reactant species in ILs [262, 263] found that in some cases the nucleophilicity of solute species depends strongly on the character of the cation, though in others the association appears to be relatively weak [264]. In some cases, desolvation of solvent ions is limited by unfavorable entropic effects rather than enthalpic ones [262], This likely relates to the highly structured nature of the solvent, which can run counter to intuitive relationships between the entropy of free and bound states. Harper and Kobrak [14] reviewed this literature in detail, and we will not discuss it further here. 

Application of these methods has revealed the limitations of certain qualitative generalizations. Thus it had been common practice to attribute the rate enhancement resulting from a change of solvent from a protic one to DMSO primarily to desolvation of the anionic nucleophiles. However, it has been shown that in a number of cases increased solvation of the transition state is the predominant factor. For example, in the reaction of p-nitrofluorobenzene with azide ion in DMSO it is found that 5A//tr(Nj) = —1-0 kcal mol-1 whilst 8AHjt = —6-5 kcal mol-1 (Cox and Parker, 1973). Similar studies, using DMSO and other dipolar aprotic media, have been carried out by Haberfield (1971), Fuchs (1974), Abraham (1974), Jones et al. (1976), and their co-workers, and will be considered in later sections. 

Though the computed free energy profile for the 8, 2 reaction in water is unimodal, it seemed likely that there should be a solvent that could yield a nonconcerted profile, that is, one with ion-molecule or solvent-separated intermediates. A solvent with diminished anion solvating ability should reduce the energy increase upon desolvation of the nucleophile. This could at least reintroduce the ion-molecule complexes as intermediates. Though hydrocar-... 

Any explanation of facial selectivity must account for the diastereoselection observed in reactions of acyclic aldehydes and ketones and high stereochemical preference for axial attack in the reduction of sterically unhindered cyclohexanones along with observed substituent effects. A consideration of each will follow. Many theories have been proposed [8, 9] to account for experimental observations, but only a few have survived detailed scrutiny. In recent years the application of computational methods has increased our understanding of selectivity and can often allow reasonable predictions to be made even in complex systems. Experimental studies of anionic nucleophilic addition to carbonyl groups in the gas phase [10], however, show that this proceeds without an activation barrier. In fact Dewar [11] suggested that all reactions of anions with neutral species will proceed without activation in the gas phase. The transition states for reactions such as hydride addition to carbonyl compounds cannot therefore be modelled by gas phase procedures. In solution, desolvation of the anion is considered to account for the experimentally observed barrier to reaction. 

When positioned in hydrophobic microenvironments, anionic nucleophiles are partially desolvated. Whether this results in acceleration, however, depends on the type of the reaction involved. If the charge is more delocalized in the transition state than in the reactant, as in 13 and 14, desolvation of the nucleophile would selectively destabilize the reactant, leading to rate enhancement. On the other hand, if the charge is more localized in the transition state, the reaction would be retarded in hydrophobic microdomains. ... 

The rates of addition of nucleophiles to carbonyl groups and the rates of elimination from the tetrahedral intermediates constitute another class, probably similar to the activated aromatic nucleophilic substitution. The carbonyl group is an electrophile, and no obvious source of any barrier exists, outside of desolvation. Therefore, a resemblance to Ritchies systems is found. No obvious relation between our kinetic nucleophilic characters (Nx) and the additions occurs, but a possible parallel to the equilibrium methylating powers, KYX (in Tables I and II), of the conjugate methylating agent of the... 

Finally, we consider the relevance of these solvated-ion studies in the gas phase to the corresponding reactions in solution. In the gas phase, the products are predominantly unsolvated in solution, they are completely solvated. In the gas phase, reaction 4 is apparently quenched by solvating the reactant with more than two solvate molecules in solution, the reaction proceeds when the reactants are infinitely solvated. This highlights the importance of the bulk solvent in solution. All pervasive, the bulk solvent can always enable the concerted desolvation of the nucleophile and solvation of the leaving group. In contrast, in the gas phase, the same solvate molecules that are released in the desolvation must be used in the solvation and if the solvate does not transfer, solvation must stop the reaction. In the gas... 

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