Solvent effects carbons, nucleophilic solvation

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. 

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). 

Taking into account the fact that the solvation of ambident anions in the activated complex may differ considerably from that of the free anion, another explanation for the solvent effect on orientation, based on the concept of hard and soft acids and bases (HSAB) [275] (see also Section 3.3.2), seems preferable [366]. In ambident anions, the less electronegative and more polarizable donor atom is usually the softer base, whereas the more electronegative atom is a hard Lewis base. Thus, in enolate ions, the oxygen atom is hard and the carbon atom is soft, in the thiocyanate ion the nitrogen atom is hard and the sulfur atom is soft, etc. The mode of reaction can be predicted from the hardness or softness of the electrophile. In protic solvents, the two nucleophilic sites in the ambident anion must interact with two electrophiles, the protic solvent and the substrate RX, of which the protic solvent is a hard and RX a soft acid. Therefore, in protic solvents it is to be expected that the softer of the two nucleophilic atoms (C versus O, N versus O, S versus N) should react with the softer acid RX. 

Comparison of the calculated nucleophilic accelerations of 9, 17, and 106 to the degree of inversion (72, 74, and 87%, respectively) for Vla-c shows that even though the kinetic effects of solvent assistance are significant, this fact does not lead to the complete inversion characteristic of the SN2 reaction as found in acetolysis of 2-octyl tosylate (45). The best description of the first intermediate in the solvolysis of Vla-c would thus appear to be the solvated ion pair shown in Scheme II. In this species, the solvent is involved in nucleophilic solvation of the central carbon as well as the remainder of the carbocation and also participates in electrophilic solvation of the anion. Numerous solvent molecules are involved, and no strong interaction of a single nucleophilic solvent molecule at the central carbon leading to exclusive inversion occurs. 

In protic solvents, the allylic carbonium ion formed by acid-catalyzed alkyl carbon-oxygen bond fission can recombine either with the carboxylic acid molecule or with a solvent molecule. The electrostatic attraction between the carbonium and carboxylate ions, which is a major factor in isomerization of allylic esters by ion-pair internal return during solvolysis, is absent in the acid-catalyzed reaction. The more numerous, usually more nucleophilic, solvent molecules in the solvation shell of the carbonium ion should compete effectively with the departed carboxylic acid molecule and solvolysis rather than isomerization should be the predominant reaction. For example, in the presence of 0.05 M perchloric acid, solvolyses of cis- and //- //7.s-5-methyl-2-cyclohexenyl p-nitrobenzoates are not only very much faster than in the absence of the acid, but polarimetric and titrimetric rates of solvolysis of optically-active esters were identical within experimental error. For these esters, the acid-catalyzed solvolysis was not accompanied by a detectable amount of isomerization. Braude reported, on the basis of indirect evidence, that isomerization accompanies acid-catalyzed hydrolysis of a-ethynyl-y-methylallyl acetate in aqueous dioxane. It was shown that, under some experimental conditions, the spectrophotometrically determined rate of appearance of the rearranged 1 -yne-3-ene chromophore exceeds the titrimetrically determined rate of hydrolysis,... 

In Wakefield s view, the solvation of the Grignard reagent makes both the Mg—C and the Mg—bonds less stable, thereby increasing the reactivity of the carbon atom and favouring the formation of the solvated RMg ion. The latter is more reactive than the undissociated molecule in both electrophilic and nucleophilic reactions. An increase in the solvating ability of the solvent beyond a certain limit, however, leads to the stabilization of the solvate of RMg" and thus to its lower reactivity. It can be seen that the above considerations may be employed to explain both a decrease and an increase in reactivity, but they are unsuitable for a prediction of the tendency and nature of the solvent effect. 

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... 

Several possible explanations have been offered. One is that the ground state of the nucleophile is destabilized by repulsion between the adjacent pairs of electrons another is that the transition state is stabilized by the extra pair of electrons a third is that the adjacent electron pair reduces solvation of the nucleophile. Evidence supporting the third explanation is that there was no alpha effect in the reaction of HOj with methyl formate in the gas phase, although HOj shows a strong alpha effect in solution. The a-efifect has been demonstrated to be remarkably dependent on the nature of the solvent. The a-effect is substantial for substitution at a carbonyl or other unsaturated carbon, at some inorganic atoms, and for reactions of a nucleophile with a carbocation, but is generally smaller or absent entirely for substitution at a saturated carbon. ... 

Some nucleophilic tendencies towards carbon are shown in Table 21. They vary by a factor of only ca. 10 within any one solvent, from the least reactive (2,4-dinitrophenoxide in MeOH) to the most reactive (e.g. CeHsS" in MeOH). If, as shown, solvation effects can produce changes of 10 in nucleophilic tendencies then it is clearly pointless, unless solvent is specified and its effect taken into account, to discuss rate data, for reactions in methanol and in other protic solvents, in terms of intrinsic properties of the nucleophile, such as structure, charge type, polarizability, hardness and softness, size, a-e fects, ability to adjust valence shells to transition state requirements, bond strength, and so on. Solvation of the nucleophile is a major factor in determining nucleophilic tendencies. 

For organic reactions in which positive charge develops on carbon, structural effects on reactivity are enhanced in weakly nucleophilic solvents (14). The effect of alkyl substitution on SN reactions can be quantified by the substituent parameter p, which is much more negative in weakly nucleophilic media [e.g., TFA (14, 20), HFIP (4), or TFE (4)] than in normal alcohol solvents. Apparently in weakly cation solvating media, the electron demand for stabilization of positive charge is met from within the molecule [e.g., by enhanced electron donation from adjacent alkyl groups (4)]. 

Synthetic Methods.—The preparation of phosphate esters by 5n2 attack of phosphate ester anions on carbon is receiving more attention following the realization that the poor nucleophilicity commonly associated with such anions is due to solvation and ion-pairing effects. Thus tetra-methylammonium di-t-butyl phosphate reacts with primary and secondary alkyl iodides in aprotic solvents to give the corresponding triesters (1) from which the t-butyl groups are readily removed by trifluoracetic acid. The proposal of a similar S 2 mechanism in the reaction of triphenylphosphine and ethyl azodicarboxylate with a phosphate diester in the presence of an... 

The alpha effect, the enhanced reactivity of nucleophiles with a lone pair of electrons on an adjacent center, has been investigated in reactions with substituted phenyl-phenyl carbonates in water/DMSO (dimethyl sulfoxide) solvent. The enhanced reactivity of oxi-mate ions, which are alpha nucleophiles, was attributed to solvation effects in the ground state rather than to transition state effects. ... 

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