Nucleophilic solvent assistance

This stereospecific reaction is, therefore, a rare example of stereochemical control by nucleophilic solvent assistance of an ionization process. 

An alternative view that also favors an intermediate mechanism is that of Schleyer and co-workers, who believe that the key to the problem is varying degrees of nucleophilic solvent assistance to ion-pair formation. They have proposed an Sn2 (intermediate) mechanism. ... 

For the methyl-substituted ethylenes, i.e. in the absence of any steric effects, there is a roughly linear relationship between the chemoselectivity and the 13C nmr chemical shift of the most substituted carbon atom of the bromonium ions (Dubois and Chretien, 1978). This selectivity is therefore discussed in terms of the magnitude of the charge on the carbon atom and the relative hardness of the competing nucleophiles, according to Pearson s theory (Ho, 1977). However, this interpretation does not take into account the substituent dependence of the nucleophilic solvent assistance, which must play a role in determining this chemoselectivity. 

In addition to the fact that steric crowding can slow the reaction by hindering bromine approach to the double bond, it appears now that bulky substituents can modify the bromination mechanism by inhibiting nucleophilic solvent assistance to ionization of the CTC and/or nucleophilic trapping of the ionic intermediates. Assistance to the rate-limiting ionization step by... 

Kinetic solvent isotope effect as a measure of electrophilic assistance to bromide ion departure limiting values rate data in ethanol, methanol and their aqueous mixtures using Bentley s TBr scale its decrease corresponds to the involvement of nucleophilic assistance. R = (/caqhtOII//cAcoH)r as a measure of nucleophilic solvent assistance. Model for a limiting bromination mechanism. Ruasse et al. (1991). /Ruasse and Zhang (1984). 9Argile and Ruasse (to be published). Modro et al. (1979). 

Table 21 Solvent effects in bromination of conjugated olefins transition-state shifts and nucleophilic solvent assistance.

The only series of alkenes that show anomalously low KSIEs is that of highly congested adamantylidenealkanes (last rows of Table 20). The decrease in the isotope effect, associated with particularly small m-values and the absence of nucleophilic solvent assistance, can be attributed to reversible... 

The first step in the interpretation of mBr-values has consisted in searching for an alkene for which nucleophilic solvent assistance is impossible. Methylideneadamantane, in which steric constraints can restrict nucleophile... 

Finally, the last group of alkenes in Table 20 (congested alkenes) behaves very differently as regards solvent effects. The mBr, R and even KSIEs are systematically smaller than those observed for the two previous series. The attenuation of these coefficients can be reasonably attributed neither to earlier transition states nor to increases in nucleophilic solvent assistance. As described in the paragraph on return (p. 279), this trend is more consistent... 

The effect of a-silyl substitution on the stability of a carbenium ion was qualitatively unclear for a long time. Early solvolytic studies by the groups of liaborn36 and Cartledge37 suggest a destabilizing effect of a-silyl substitution compared with alkyl. The measurement and interpretation of the kinetic a-silicon effect in solvolysis reactions is, however, often complicated by the fact that steric and ground state effects may play an important role and that, in addition, the rates of ionization often involve a contribution from nucleophilic solvent assistance. 

In contrast to typical mono- or acyclic substrates (e. g.,isopropyl), 2-adaman-tyl derivatives are also found to be insensitive to changes in solvent nucleophilicity. A variety of criteria, summarized in Table 13, establish this point. In all cases, the behavior of 2-adamantyl tosylate is comparable to that observed for its tertiary isomer but quite unlike that observed for the isopropyl derivative. Significant nucleophilic solvent participation is indicated in the solvolysis reactions of the isopropyl system. The 2-adamantyl system, on the other hand, appears to be a unique case of limiting solvolysis in a secondary substrate 296). The 2-adamantyl/ isopropyl ratios in various solvents therefore provide a measure of the minimum rate enhancement due to nucleophilic solvent assistance in the isopropyl system 297). 

Furthermore, using their scale of nucleophilic solvent assistance, Bentley and Schleyer (Schadt et al, 1976 Bentley and Schleyer, 1977) have shown... 

To limit the scope of this review and to reduce overlap with other reviews, some related topics will only be discussed briefly. The addition of salts can affect both the rate and the course of solvolytic reactions and provides very important evidence for ion-pair intermediates. A full discussion of this topic has been published recently (Raber etal., 1974) additional comments are given onpp. 27,32. Also, we have generally excluded solvolyses known to proceed by competitive nucleophilically solvent-assisted and anchimerically assisted pathways. These solvolyses are very common (e.g. even n-propyl tosylate yields 87% of rearranged product during trifluoroacetolysis Reich et al., 1969), but a detailed account has been published recently (Harris, 1974). Recognition that solvolytic reactions could proceed by these two competitive, assisted pathways provided the key to the solution of the controversial phenonium ion problem (Lancelot et al., 1972 Brown et al., 1970), as well as inspiring the reinvestigation of the mechanisms of solvolyses of simple secondary substrates discussed in Section 2. 

Nucleophilic Solvent Assistance—kinetically significant involvement of the solvent as nucleophile or base by partial bonding (as distinct from general electrostatic solvation) to any atom of the substrate (e.g. a-carbon, j3-hydrogen, etc.) ... 

In order to fit solvolytic reactions into the above framework it is important to establish the magnitude of nucleophilic solvent assistance, the extent to which nucleophilic attack by solvent assists heterolytic cleavage of the bond to the leaving group. 2-Adamantyl tosylate [6] was selected as a model for SN 1 behaviour because non-bonded interactions [7] would reduce the possibility of nucleophilic attack (Fry et al., 1970a) extensive experimental evidence... 

The most likely direction of errors in these three assumptions are such that the calculations of Schleyer et al. (1970) will underestimate the magnitude of nucleophilic solvent assistance.2 This can readily be seen for assumptions (a) and (6), but for assumption (c) it will be shown later that the major deviations from Fig. 20 are such that the calculated rate constants are too small. If there is an... 

Minimum Estimates of Nucleophilic Solvent Assistance (Equation 2)a... 

An independent method for estimating nucleophilic solvent assistance has been applied to solvolyses of bromides with similar results (Fry et al., 1970b). In this approach, secondary solvolyses are compared with solvolyses of the corresponding tertiary substrates (e.g. 2-propyl compared with t-butyl). Again the reference substrate was 2-adamantyl (and 2-methyl-2-adamantyl [8]). It was found that... 

Presumably less nucleophilically assisted solvolyses could show higher a-deuterium isotope effects, and there is a linear relationship between the magnitude of nucleophilic solvent assistance (Table 2) and the a-deuterium isotope effect for solvolyses of 2-propyl sulpho-nates (Fig. 7). Another measure of nucleophilic assistance is the ratio k2 (OH )/, where k2 is the second-order rate constant for nucleophilic attack by OH and kx is the first-order rate constant for reaction with the solvent water, and a linear correlation was obtained by plotting the ratio versus the experimentally observed isotope effects for methyl and trideuteriomethyl sulphonates, chlorides, bromides and iodides (Hartman and Robertson, 1960). Using fractionation factors the latter correlation may also be explained by a leaving group effect on initial state vibrational frequencies (Hartshorn and Shiner, 1972), but there seems to be no sound evidence to support the view that Sn2 reactions must give a-deuterium isotope effects of 1-06 or less. 

Figure 7. Correlation of a-deuterium isotope effect (Ah/ D) and magnitude of nucleophilic solvent assistance for 2-propyl sulphonates (data from Schadt et al., 1976, and TableS). Abbreviations for solvents T = wt% trifluoroethanol/water E=vol% ethanol/ water.

The solvent acts as a kinetically significant nucleophile in the overall solvolysis process for many simple secondary substrates, and this appears to be the major cause of the variation in relative rates with changes in solvent (Table 2, p. 11). This conclusion is supported by the quantitative correlations discussed in Section 6. The stereochemical evidence further suggests that, even when the magnitude of nucleophilic solvent assistance is less than a rate factor of 10 at 25°, solvolyses (e.g. of cylcohexyl tosylate in formic acid) can proceed with essentially complete inversion of configuration. These results are consistent with an SN 2 mechanism and the evidence for ion pair intermediates can then be considered in one of two ways. 

It may be argued that the evidence for ion pair intermediates is too indirect, since it has not been established that the ion pairs undergoing 18 O-scrambling or interned return are the same as those undergoing solvolysis. Evidence for ion pairs would then be explained by side-reactions and the solvolytic reactions for which nucleophilic solvent assistance is greater... 

Alternatively, if it is accepted that ion pairs are involved in the solvolysis process and that nucleophilic solvent assistance is also significant, then the reaction might proceed via a nucleo-philically-solvated ion-pair intermediate (e.g. [34], Fig. 8). 

A change of mechanism from SN1 to Sn2 can be envisaged (Fig. 9) to involve an increase in the magnitude of nucleophilic solvent assistance from zero (SN 1). We suggest that solvolyses for which nucleophilic solvent assistance is greater than a rate factor of 10 (Table 2) should be classified as Sn2.s This includes many solvolyses... 

Other evidence to support the selection of 2-adamantyl tosylate as model compound has been discussed in Section 2 (p. 8), and the main conclusion can be summarized as follows. Independent evidence and the results in Fig. 15 firmly establish that nucleophilic solvent assistance cannot be appreciable for solvolyses of 2-adamantyl tosylate, since its response to solvents of widely varying nucleophilicities is almost exactly the same as 1-bicyclo [2,2,2] octyl tosylate [49] for which rearside attack is impossible if solvolyses of 2-adamantyl tosylate are anchimerically assisted, the extent of anchimeric assistance does not appear to be dependent on solvent (cf. Pritt and Whiting, 1975). In addition to these conclusions, the results in Fig. 14 suggest that internal return from intermediate contact ion pairs does not occur to a detectable extent for solvolyses of 2-adamantyl tosylate (see also Bentley and Schleyer, 1976). 

Perhaps the most spectacular success of explanations based on solvation of ground states, published to date, is the dissection of activation parameters for solvolysis of t-butyl chloride in mixtures of ethanol and water, first discussed by Winstein and Fainberg (1957). The complex variation of AH and AS (Fig. 21) has been shown to be due almost entirely to ground state solvation effects, at least for the solvents ethanol—40% ethanol/water studied by Arnett et al. (1965). For 90%, 80%, 70%, 60%, 50% and 40% ethanol/water the parameter AH1 for solvation of the transition state (by transfer from the gas phase) was calculated to be linearly proportional to the corresponding value of AS, as expected from the behaviour of simple salts. The point for pure ethanol did not fall on the calculated line, and this was attributed to nucleophilic solvent assistance. The variation in AG, AH and AS (Fig. 21) can be reproduced remarkably well using ethane and the zwitterionic a-amino acid, glycine, as model compounds (Abraham et al., 1975 see also Abraham, 1974 Abraham and Abraham, 1974). 

Raber et al. (1971b) noted that, in addition to 2-octyl mesylate, a number of primary and secondary substrates which also underwent solvolysis with substantial nucleophilic solvent assistance all showed considerably higher selectivities than expected from the reactivity-selectivity relationship illustrated in Fig. 8. They concluded that, while the failure of these points to correlate with the carbocations did point to a mechanistic difference between the two groups, the conclusion... 

---