Nucleophiles solvolysis

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. 

The hydroxy group can act as an intramolecular nucleophile. Solvolysis of 4-chlorobutanol in water gives as the product the cyclic ether tetrahydrofuran. The reaction is much faster than solvolysis of 3-chloropropanol under similar conditions. 

Simple kinetic measurements can, however, be an inadequate guide to which of the above two mechanisms, SN1 or SN2, is actually operating in, for example, the hydrolysis of a halide. Thus, as we have seen (p. 45), where the solvent can act as a nucleophile (solvolysis), e.g. H20, we would expect for an S 2 type reaction,... 

In this review, the chemical properties of these electrophilic metabolites (i-XIIl) are discussed in terms of their metabolic formation and reactivity with nucleophiles, solvolysis and redox characteristics, reaction mechanisms, and their role as ultimate carcinogenic metabolites. 

Let us turn briefly to the special case of nucleophilic aliphatic substitution in which the solvent is the nucleophile solvolysis. In its various aspects, solvolysis is— and has been for many years—the most intensively studied reaction in organic chemistry. Yet it is the reaction about which there is probably the most intense disagreement. 

The experimental data obtained in the OH -catalyzed hydrolyses of styrene oxides are completely different from the ones previously commented. First, the reaction products result from the incorporation of the nucleophile (OH ) to both, the a and the P positions of the oxirane ring, as it has been demonstrated in the reaction with K 0H/H2 0. Second, a change in the nucleophile (solvolysis in MeO /MeOH) does not make any major difference, and again both products resulting from the a-and the P-attack are obtained (Scheme 11.6). 

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... 

Suggest a structure for the product of nucleophilic substitution obtained on solvolysis of tert-butyl bromide in methanol and outline a reason able mechanism for its formation... 

Tertiary alkyl halides are so sterically hindered to nucleophilic attack that the pres ence of any anionic Lewis base favors elimination Usually substitution predominates over elimination m tertiary alkyl halides only when anionic Lewis bases are absent In the solvolysis of the tertiary bromide 2 bromo 2 methylbutane for example the ratio of substitution to elimination is 64 36 m pure ethanol but falls to 1 99 m the presence of 2 M sodium ethoxide... 

When applied to the synthesis of ethers the reaction is effective only with primary alcohols Elimination to form alkenes predominates with secondary and tertiary alcohols Diethyl ether is prepared on an industrial scale by heating ethanol with sulfuric acid at 140°C At higher temperatures elimination predominates and ethylene is the major product A mechanism for the formation of diethyl ether is outlined m Figure 15 3 The individual steps of this mechanism are analogous to those seen earlier Nucleophilic attack on a protonated alcohol was encountered m the reaction of primary alcohols with hydrogen halides (Section 4 12) and the nucleophilic properties of alcohols were dis cussed m the context of solvolysis reactions (Section 8 7) Both the first and the last steps are proton transfer reactions between oxygens... 

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

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... 

Nucleophilic substitution reactions that occur imder conditions of amine diazotization often have significantly different stereochemisby, as compared with that in halide or sulfonate solvolysis. Diazotization generates an alkyl diazonium ion, which rapidly decomposes to a carbocation, molecular nitrogen, and water ... 

A classic example of neighboring-group participation involves the solvolysis of compounds in which an acetoxy substituent is present next to a carbon that is undergoing nucleophilic substitution. For example, the rates of solvolysis of the cis and trans isomers of 2-acetoxycyclohexyl p-toluenesulfonate differ by a factor of about 670, the trans compound being the more reactive one ... 

Like the un-ionized hydroxyl group, an alkoxy group is a weak nucleophile. Nevertheless, it can operate as a neighboring nucleophile. For example, solvolysis of the isomeric p-bromobenzenesulfonate esters 6 and 7 leads to identical prxKluct nuxtures, suggesting the involvement of a common intermediate. This can be explained by involvement of the cyclic oxonium icai which would result from intramolecular participation. ... 

The occurrence of nucleophilic participation is also indicated by a rate enhancement relative to the rate of solvolysis of n-butyl p-bromobenzenesulfonate. The solvolysis rates of a series of cu-mefhoxyall l p-bromobenzenesulfontes have been determined. A maximum rate is again observed where participation of a methoxy group via a live-membered ring is possible (see Table 5.20). 

Studies of the solvolysis of 1-phenylethyl chloride and its p-substituted derivatives in aqueous trifluorethanol containing azide anion as a potential nucleophile provide details relative to the mechanism of nucleophilic substitution in this system. 

The relative solvolysis rates in 50% ethanol—water of four isomeric p-bromobenze-nesulfonates are given below. R and T give an identical product mixture comprised of V and W, whereas S gives X and Y. Analyze these data in terms of possible participation of the oxygen atom in nucleophilic substitution. 

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