Solvents Solvolysis

Nucleophile Weak Lewis base, neutral molecule, nucleophile may be the solvent (solvolysis) Strong Lewis base, rate favored by high concentration of nucleophile... 

Most of the prepared heteroles are soluble in less polar solvents such as hexane(s), benzene, toluene, diethyl ether, THF, dioxane, CHCI3, CH2CI2, etc. Generally, the target compounds are less stable in polar solvents (solvolysis) or under exposure on air. The most frequent isolation is based on extraction or precipitation of by-products or unreacted reagents (Table 8). 

If solvolysis of CMP- NeuAc required nucleophilic participation of the carboxylate, this would proceed via a transient a-lactone, and in a second step give net retention to afford the p-anomcr. A direct displacement of CMP by solvent without carboxylate participation would yield the a-anomer, while a transition state that resulted in formation of a sialyl oxocarbenium ion would proceed with results ranging from inversion to racemization depending on whether the oxocarbenium ion lived long enough to equilibrate with solvent. Solvolysis of CMP-NeuAc in meth-anol/water mixtures at pH 5.0, resulted in 1 1 ratios of a- and p-methyl glycosides of NeuAc as determined by H-NMR.31 The a/p-methyl glycoside ratio was invariant when the mol fraction of methanol was increased by over 50%, which shows... 

The reduction of sulphonyl halides RS02X may occur whatever the (aliphatic or aromatic) nature of the R group. Disturbances may be caused either by the solvent (solvolysis with breaking of the S—X bond) or the electrode (interaction between the sulphonyl halide and the mercury). All presently available data concern exclusively the chloride (X = Cl). 

The addition of acids to olefins, since it involves the formation of a carbonium ionic species, will be subject to a number of side reactions which divert the course of the reaction by providing other routes through which the carbonium ion may be attacked. In a hydroxylic solvent, solvolysis of the carbonium may occur preferentially to the reaction with X (Scheme 3.), or polymerisation or cyclization may take place. 

Mechanistic chemists continue to explore and exploit the interesting solvent properties of 2,2,2-trifluoroethanol however, the propanol (CF8)aCH-OH possesses a higher ionizing power and an even lower nucleophilidty than CFs-CHs-OH while still being much less acidic than trifluoroacetic add, so it ought to attract the greater attention in future. With both these solvents, solvolysis kinetics can be followed conveniently and accurately by conductivity techniques 97 wt.% RrOH/HzO [Rf = CFs-CHs or (CF8)aCH] is employed). 

The Lewis base that acts as the nucleophile often is but need not always be an anion Neutral Lewis bases can also serve as nucleophiles Common examples of substitutions involving neutral nucleophiles include solvolysis reactions Solvolysis reactions are substitutions m which the nucleophile is the solvent m which the reaction is carried out 8olvolysis m water (hydrolysis) converts an alkyl halide to an alcohol... 

Analogous reactions take place in other solvents which like water contain an —OH group Solvolysis in methanol (methanolysis) gives a methyl ether... 

Solvent Effects on the Rate of Substitution by the S l Mechanism Table 8 6 lists the relative rate of solvolysis of tert butyl chloride m several media m order of increasing dielectric constant (e) Dielectric constant is a measure of the ability of a material m this case the solvent to moderate the force of attraction between oppositely charged par tides compared with that of a standard The standard dielectric is a vacuum which is assigned a value e of exactly 1 The higher the dielectric constant e the better the medium is able to support separated positively and negatively charged species 8olvents... 

Relative Rate of SnI Solvolysis of te/t-Butyl Chloride as a Function of Solvent Polarity ... 

Ratio of first order rate constant for solvolysis in indicated solvent to that for solvolysis in acetic acid at 25 C... 

Solvolysis reaction (Section 8 7) Nucleophilic substitution m a medium m which the only nucleophiles present are the solvent and its conjugate base... 

Alkanesulfinyl chlorides have been prepared by the action of thionyl chloride on alkanesulfinic acids and by the solvolysis of alkylsulfur trichlorides with water, alcohols, and organic acids. The present procedure, which appears to be general for the preparation of sulfinyl chlorides in either the aliphatic or the aromatic series, is based on an improvement in the solvolysis method whereby the use of inert solvent is eliminated and the reaction is carried out in a one-phase system. ... 

A scale for solvent ionizing power, K+, applicable in solvolysis reactions of cationic substrates, has been developed. For example,... 

The points that we have emphasized in this brief overview of the S l and 8 2 mechanisms are kinetics and stereochemistry. These features of a reaction provide important evidence for ascertaining whether a particular nucleophilic substitution follows an ionization or a direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the Sj l mechanism and those exhibiting second-order kinetics react by the 8 2 mechanism. Many nucleophilic substitutions are carried out under conditions in which the nucleophile is present in large excess. When this is the case, the concentration of the nucleophile is essentially constant during die reaction and the observed kinetics become pseudo-first-order. This is true, for example, when the solvent is the nucleophile (solvolysis). In this case, the kinetics of the reaction provide no evidence as to whether the 8 1 or 8 2 mechanism operates. 

Winstein suggested that two intermediates preceding the dissociated caibocation were required to reconcile data on kinetics, salt effects, and stereochemistry of solvolysis reactions. The process of ionization initially generates a caibocation and counterion in proximity to each other. This species is called an intimate ion pair (or contact ion pair). This species can proceed to a solvent-separated ion pair, in which one or more solvent molecules have inserted between the caibocation and the leaving group but in which the ions have not diffused apart. The free caibocation is formed by diffusion away from the anion, which is called dissociation. 

The importance of solvent participation in the borderline mechanisms should be noted. Nucleophilic participation is minimized by high electronegativity, which reduces the Lewis basicity and polarizability of the solvent molecules. Trifluoroacetic acid and perfiuoro alcohols are among the least nucleophilic of the solvents used in solvolysis studies. These solvents are used to define the characteristics of reactions proceeding without nucleophilic solvent participation. Solvent nucleophilicity increases with the electron-donating capacity of the molecule. The order trifluoroacetic acid < trifluoroetha-nol <acetic acid < water < ethanol gives a qualitative indication of the trend in solvent nucleophilicity. More will be said about solvent nucleophilicity in Section 5.5. 

In interpreting many aspects of displacement reactions, particularly solvolysis, it is important to be able to characterize fee nucleophilicity of fee solvent. Assessment of... 

Table S.16 presents data on some representative nucleophilic substitution processes. The first entry illustrates the use of 1-butyl-l-r/p-bromobenzenesulfonate to dononstrate at primary systems react with inversion, even under solvolysis conditkms in formic acid. The observation of inversion indicates a concerted mechanism in fids weakly nucleophilic solvent.

Nucleophilic substitution in cyclohexyl systems is quite slow and is often accompanied by extensive elimination. The stereochemistry of substitution has been determined with the use of a deuterium-labeled substrate (entry 6). In the example shown, the substitution process occurs with complete inversion of configuration. By NMR amdysis, it can be determined that there is about 15% of rearrangement by hydride shift accon any-ing solvolysis in acetic acid. This increases to 35% in formic acid and 75% in trifiuoroacetic acid. The extent of rearrangement increases with decreasing solvent... 

Stabilization of a carbocation intermediate by benzylic conjugation, as in the 1-phenylethyl system shown in entry 8, leads to substitution with diminished stereosped-ficity. A thorough analysis of stereochemical, kinetic, and isotope effect data on solvolysis reactions of 1-phenylethyl chloride has been carried out. The system has been analyzed in terms of the fate of the intimate ion-pair and solvent-separated ion-pair intermediates. From this analysis, it has been estimated that for every 100 molecules of 1-phenylethyl chloride that undergo ionization to an intimate ion pair (in trifluoroethanol), 80 return to starting material of retained configuration, 7 return to inverted starting material, and 13 go on to the solvent-separated ion pair. 

When enantiomerically pure fni/is-2-acetoxycyclohexyl tosylate is solvolyzed, tiie product is racemic /mn -diacetate. This is consistent with the proposed mechanism, since the acetoxonium intennediate is achiral and can only give rise to racemic material. Additional evidence for diis interpretation comes from the isolation of a cyclic ortho ester when the solvolysis is carried out in ethanol. In this solvent the acetoxonium ion is captured by the solvent. 

Table 5.22. Extent of Solvolysis with Aryl Participation as a Function of Substituent and Solvent for l-Aryl-2-propyl Tosylates...

The occurrence and extent of rearrangement of the 2-butyl cation have also been investigated by solvolysis studies using isotopic labeling. When 2-butyl tosylate is solvolyzed in acetic acid, C-2/C-3 rearrangement occurs only to the extent of 9% in the 2-butyl acetate which is isolated.Thus, under these conditions, most of the reaction proceeds by direct participation of the solvent. 

Let us now return to the question of solvolysis and how it relates to the stracture under stable-ion conditions. To relate the structural data to solvolysis conditions, the primary issues that must be considered are the extent of solvent participation in the transition state and the nature of solvation of the cationic intermediate. The extent of solvent participation has been probed by comparison of solvolysis characteristics in trifluoroacetic acid with the solvolysis in acetic acid. The exo endo reactivity ratio in trifluoroacetic acid is 1120 1, compared to 280 1 in acetic acid. Whereas the endo isomer shows solvent sensitivity typical of normal secondary tosylates, the exx> isomer reveals a reduced sensitivity. This indicates that the transition state for solvolysis of the exo isomer possesses a greater degree of charge dispersal, which would be consistent with a bridged structure. This fact, along with the rate enhancement of the exo isomer, indicates that the c participation commences prior to the transition state being attained, so that it can be concluded that bridging is a characteristic of the solvolysis intermediate, as well as of the stable-ion structure. ... 

The solvolysis of the tosylate of 3-cyclohexenol has been studied in several solvents. The rate of solvolysis is not very solvent-sensitive, being within a factor of 5 for all solvents. The product distribution is solvent-sensitive, however, as shown below. 

In the solvolysis reaetion, HjO is the solvent as well as a reaetant, and it is present in large exeess. It does not appear in the rate equation, whieh is expressed by... 

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