Solvation of nucleophiles

For carbon-carbon bond-formation purposes, S 2 nucleophilic substitutions are frequently used. Simple S 2 nucleophilic substitution reactions are generally slower in aqueous conditions than in aprotic organic solvents. This has been attributed to the solvation of nucleophiles in water. As previously mentioned in Section 5.2, Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions (Scheme 6.1). In alkylations of phenoxide ions by benzylic chlorides, S/y2 substitutions can occur both at the phenoxide oxygen and at the ortho and para positions of the ring. In fact, carbon alkylation occurs in water but not in nonpolar organic solvents and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para). The effects of phenol substituents and of cosolvents on the rates of the competing alkylation processes... 

Solvation of nucleophilic reagents and leaving groups causes enormous differences in the behavior of reactions in the gas phase and in solution (i). However, it is not so clear how solvation effects are manifested in the experimental data for reactions in a given solvent. A tendency for... 

The first step of the Sfjl mechanism involves the formation of ions. Since polar solvents can solvate ions, the rate of Sjj 1 processes is enhanced by polar solvents. On the other hand, solvation of nucleophiles ties up their unshared electron pairs. Therefore, Sfj2 reactions, whose rates depend on nucleophile effectiveness, are usually retarded by polar protic solvents. Polar but aprotic solvents [examples are acetone, dimethyl sulfoxide, (CH3)2S=0, or dimethylformamide, (CH3)2NCHO] solvate cations preferentially. These solvents accelerate 8 2 reactions because, by solvating the cation (say, K in K CN), they leave the anion more naked or unsolvated, thus improving its nucleophilicity. 

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)... 

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... 

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. ... 

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. 

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. 

As pointed out by Chapman et the steric requirements of the reagents and the degree of solvation of the substrate at the reacting center should also be considered when comparing the nucleophilicities of different amines toward different substrates. The large number of factors which may be involved clearly call for much more work in this area. 

The effect of solvation of transition states has been discussed in relation to aromatic nucleophilic substitution. 

As the size of the nucleophile increases, reaction adjacent to a solvated azine-nitrogen or to a quatemized ring-nitrogen will be sterically hindered. The very large decelerative effect o > of solvation of the nucleophile in aromatic substitution is mentioned in Section I, D, 2, d. 

Aromatic denitrocyclizations have been used for many years in some well-known synthetic reactions. Probably the best known example is the Turpin synthesis of phenoxazines and similar synthesis of phenothiazines. The classical setup used usually base-catalyzed reactions in polar protic solvents, very often alcohols. In many cases using polar aprotic solvents was found advantageous. Besides the mentioned influence of the H-bonding, better ionization and lower solvation of the nucleophile are also important. Sf Ar reactions proceed through strongly polarized complexes, which are well soluble and highly polarized in polar aprotic solvents. 

Protic solvents, such as methanol and ethanol, slow down SN2 reactions by solvation of the reactant nucleophile. The solvent molecules hydrogen bond to the nucleophile and form a "cage" around it, thereby lowering its energy and reactivity. 

Carboxylic acids have also been investigated as nucleophiles in the ring-opening of aziridine-2-carboxylates [103]. Solvation of compounds 129 (Scheme 3.46) in acetic acid, for example, gave 130a and 130b in 83% and 89% yields, respectively. 

In these solvents at sufficiently low Br2 concentration (< 10-3 m) the kinetics are first order both in the olefin and in Br2 and the main solvent effect consists of an electrophilic solvation of the departing Br ion. A nucleophilic assistance by hydroxylic solvents has also been recognized recently (ref. 26) (Scheme 10). So far, return during the olefin bromination in methanol had been admitted only for alkylideneadamantanes, and was ascribed to steric inhibition to nucleophilic attack at carbons of the bromonium ion (ref. 26). 

The first step is a slow ionization of the substrate and is the rate-determining step. The second is a rapid reaction between the intermediate carbocation and the nucleophile. The ionization is always assisted by the solvent, since the energy necessary to break the bond is largely recovered by solvation of R" " and of X. For example, the ionization of f-BuCl to f-Bu" and Cl" in the gas phase without a solvent requires ISOkcalmol" (630kJmol" ). In the absence of a solvent such a process simply would not take place, except at very high temperatures. In water, this... 

In Chapter 3, we saw that cryptands specifically solvate the alkali metal portion of salts like KF, KOAc, and so on. Synthetic advantage can be taken of this fact to allow anions to be freer, thus increasing the rates of nucleophilic substitutions and other reactions (see p. 455). 

The possible mechanisms for solvolysis of phosphoric monoesters show that the pathway followed depends upon a variety of factors, such as substituents, solvent, pH value, presence of nucleophiles, etc. The possible occurrence of monomeric metaphosphate ion cannot therefore be generalized and frequently cannot be predicted. It must be established in each individual case by a sum of kinetic and thermodynamic arguments since the product pattern frequently fails to provide unequivocal evidence for its intermediacy. The question of how free the PO ion actually exists in solution generally remains unanswered. There are no hard boundaries between solvation by solvent, complex formation with very weak nucleophiles such as dioxane or possibly acetonitrile, existence in a transition state of a reaction, such as in 129, or SN2(P) or oxyphosphorane mechanisms with suitable nucleophiles. 

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