Nucleophilicity solvation

A rare case of preferential 2-attack occurs with potassium hydroxide in t-butanol. Here, this result has been attributed to the large steric requirement of the solvated nucleophile, and the fact that the 4-position is the most crowded site. Consequently, it is observed that 3,5-dichlorotrifluoropyridine gives preferential 2-attack with this reagent [102] (Figure 9.37). 

The addition of a nucleophile to a carbonyl compound with a chiral a carbon generates a mixture of two diastereoisomers. The ratio of these diastereoisomers depends on the relative bulks of the (non-coordinating) substituents on the chiral center, the effective bulkiness of the nucleophile as well and the reaction conditions. By effective bulkiness, we mean the bulk of the solvated nucleophile, if the same is imminent. The reaction is schematically represented in Eq. 1. 

This 10-fold rate decrease means that these anionic oxygen nucleophiles react only approximately one time in 10 when they diffuse up to the carbo-cation. If diffusion of the solvated nucleophile toward the carbocation gives the solvent-separated ion pair I in equation 6 as the initial product, the ion pair diffuses apart about 10 times for every time that it loses water to form the intimate ion pair, which collapses rapidly to product. This finding suggests... 

A solvated nucleophile must shed some of its solvent molecules to react with the substrate. In a polar aprotic solvent, the nucleophile is less unencumbered by solvent molecules because hydrogen bonding between the solvent and the nucleophile is not possible. 

For a strongly solvated nucleophile to react, it must shed some of its solvent molecules so that it can approach the carbon of the substrate that bears the leaving group. This is one type of important solvent effect in nucleophilic reactions. 

Figure 6 Observed variations with the number of solvent molecules in the rate coefficient for nucleophilic-displacement reactions between various solvated nucleophiles and methyl chloride at room temperature. The measurements were taken using the flowing-afterglow technique. Reproduced with permission from Bohme DK and Raksit AB (1984) Journal of the American Chemical Society 06 3447-3452.

The order of nucleophilicity is opposite to the order of basicity for nucleophiles derived from atoms in the same group of the periodic table. First, consider the nucleophihcities of methane thiolate (CH3S ) and methoxide (CHjO"). Methane thiol is a stronger acid (pA = 10.6) than methanol (pAT = 15.5), and methoxide is therefore a stronger base than methane thiolate. However, methane thiolate is much more nucleophUic than methoxide (Table 10.1). The ratio of the relative rates for methylthiolate and methoxide in the displacement of iodide from methyl iodide is about 500 to 1. To react, a solvated nucleophile must lose some solvent molecules, so the nucleophile can approach the carbon center and start to form a bond to it. Therefore, its nucleophUicity is greatly decreased. 

Polar protic solvents favor ionization and hence S l reactions. Polar aprotic solvents, unable to solvate nucleophiles, favor Sfg2 processes. 

Example Solvation can have a profound effect on the potential energy profile for a reaction. Jorgensen s research group provided important insights into the role of solvation. Consider the nucleophilic addition of the hydroxide anion to formaldehyde ... 

Rate increases with increasing po larity of solvent as measured by its dielectric constant e (Section 8 12) Polar aprotic solvents give fastest rates of substitution solvation of Nu IS minimal and nucleophilicity IS greatest (Section 8 12)... 

In media such as water and alcohols fluoride ion is strongly solvated by hydro gen bonding and is neither very basic nor very nucleophilic On the other hand the poorly solvated or naked fluoride 10ns that are present when potassium fluoride dis solves m benzene m the presence of a crown ether are better able to express their anionic reactivity Thus alkyl halides react with potassium fluoride m benzene containing 18 crown 6 thereby providing a method for the preparation of otherwise difficultly acces sible alkyl fluorides... 

Solvent for Displacement Reactions. As the most polar of the common aprotic solvents, DMSO is a favored solvent for displacement reactions because of its high dielectric constant and because anions are less solvated in it (87). Rates for these reactions are sometimes a thousand times faster in DMSO than in alcohols. Suitable nucleophiles include acetyUde ion, alkoxide ion, hydroxide ion, azide ion, carbanions, carboxylate ions, cyanide ion, hahde ions, mercaptide ions, phenoxide ions, nitrite ions, and thiocyanate ions (31). Rates of displacement by amides or amines are also greater in DMSO than in alcohol or aqueous solutions. Dimethyl sulfoxide is used as the reaction solvent in the manufacture of high performance, polyaryl ether polymers by reaction of bis(4,4 -chlorophenyl) sulfone with the disodium salts of dihydroxyphenols, eg, bisphenol A or 4,4 -sulfonylbisphenol (88). These and related reactions are made more economical by efficient recycling of DMSO (89). Nucleophilic displacement of activated aromatic nitro groups with aryloxy anion in DMSO is a versatile and useful reaction for the synthesis of aromatic ethers and polyethers (90). 

Reactant structure will also influence the degree of nucleophilic solvent participation. Solvation is minimized by steric hindrance. The 2-adamantyl system is regarded as being a... 

Many properties have an influence on nucleophilicity. Those considered to be most significant are (1) the solvation energy of the nucleophile (2) the strength of the bond being formed to carbon (3) the size of the nucleophile (4) flie electronegativity of the attacking atom and (5) the polarizability of the attacking atom. Let us consider how each of these factors affects nucleophilicity ... 

In fee absence of fee solvation typical of protic solvents, fee relative nucleophilicity of anions changes. Hard nucleophiles increase in reactivity more than do soft nucleophiles. As a result, fee relative reactivity order changes. In methanol, for example, fee relative reactivity order is N3 > 1 > CN > Br > CP, whereas in DMSO fee order becomes CN > N3 > CP > Br > P. In mefeanol, fee reactivity order is dominated by solvent effects, and fee more weakly solvated N3 and P ions are fee most reactive nucleophiles. The iodide ion is large and very polarizable. The anionic charge on fee azide ion is dispersed by delocalization. When fee effect of solvation is diminished in DMSO, other factors become more important. These include fee strength of fee bond being formed, which would account for fee reversed order of fee halides in fee two series. There is also evidence fiiat S( 2 transition states are better solvated in protic dipolar solvents than in protic solvents. 

Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs wifii complete inversion. The results cited in entry 5 serve to illustrate the importance of solvation of ion-pair intermediates in reactions of secondary substrates. The data show fiiat partial racemization occurs in aqueous dioxane but that an added nucleophile (azide ion) results in complete inversion, both in the product resulting from reaction with azide ion and in the alcohol resulting from reaction with water. The alcohol of retained configuration is attributed to an intermediate oxonium ion resulting from reaction of the ion pair with the dioxane solvent. This would react until water to give product of retained configuratioiL When azide ion is present, dioxane does not efiTectively conqiete for tiie ion-p intermediate, and all of the alcohol arises from tiie inversion mechanism. ... 

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