Solvolysis of Secondary Substrates

Detailed discussions in this section will be restricted to the solvolyses of simple secondary substrates, i.e. those possessing saturated secondary alkyl groups which do not undergo neighbouring group participation. Solvolyses of other secondary substrates involving ion pair intermediates have recently been reviewed (Raber et al., 1974). 

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The variety of difficulties encountered when trying to fit the solvolysis of secondary substrates into the Sn 2-Sn 1 framework has led to much research and much discussion of the mechanisms of these reactions. Consideration has been given to intermediate mechanisms, possibly involving ion pairs, as well as to a spectrum of mechanisms between the SN 2 and SN 1 extremes. Since a vague theory cannot be proved wrong (Feynman, 1965), scientific progress... 

The rate enhancement in the solvolysis of secondary cyclobutyl substrates is probably caused by participation by a bond leading directly to 58, which accounts for the fact that solvolysis of cyclobutyl and... 

This rearrangement, which accounts for the scrambling, is completely stereospecific.The rearrangements probably take place through a nonplanar cyclobutyl cation intermediate or transition state. The formation of cyclobutyl and homoallylic products from a cyclopropylmethyl cation is also completely stereospecific. These products may arise by direct attack of the nucleophile on 65 or on the cyclobutyl cation intermediate. A planar cyclobutyl cation is ruled out in both cases because it would be symmetrical and the stereospecificity would be lost, iv. The rate enhancement in the solvolysis of secondary cyclobutyl substrates is probably caused by participation by a bond leading directly to 65, which accounts for the fact that solvolysis of cyclobutyl and of cyclopropylmethyl... 

Table 5 shows that for tertiary systems the exo endo rate ratio predicted only with steric factors agrees with experiments in the case of secondary systems there is no such accordance. Thus the difference in activation ener for the solvolysis of secondary exo- and endo-derivatives which is due to the a-participation upon solvolysis of exo isomer coincides by chance with the difference for tertiary systems due to a steric strain decrease in the transition state for exo isomers owing to the removal of 2-endo-alkyl from 6-endo-hydrogen The relief of the steric strain in the transition state of solvolysis of 2-exo-esters makes it necessary to correct for the steric accelerating effect in tertiary systems in comparing tertiary and secondary substrates. 

The special salt effect is another factor that requires at least two ion-pair intermediates to be adequately explained. Addition of salts typically causes an increase in the rate of solvolysis of secondary alkyl arenesulfonates that is linear with salt concentration. The effect of added lithium perchlorate is anomalous toward certain substrates in producing an initial sharp increase in the solvolysis rate, followed by the expected linear increase at higher lithium perchlorate concentrations. Winstein ascribed this to interaction of lithium perchlorate with the solvent-separated ion pair to form a solvent-separated carbonium ion perchlorate ion pair that does not undergo return to the intimate ion pair or covalent substrate. This new ion pair can go on only to product, and its formation leads to an increase in solvolysis rate more pronounced than for a simple medium effect. 

These observations suggest that the mechanism of solvolysis of secondary and, especially, tertiary haloalkanes must be different from that of bimolecular substitution. To understand the details of this transformation, we shall use the same methods that we used to study the Sn2 process kinetics, stereochemistry, and the effect of substrate structure and solvent on reaction rates. 

There is an ongoing controversy about whether there is any stabilization of the transition state for nucleophilic substitution at tertiary aliphatic carbon from interaction with nucleophilic solvent." ° This controversy has developed with the increasing sophistication of experiments to characterize solvent effects on the rate constants for solvolysis reactions. Grunwald and Winstein determined rate constants for solvolysis of tert-butyl chloride in a wide variety of solvents and used these data to define the solvent ionizing parameter T (Eq. 3). They next found that rate constants for solvolysis of primary and secondary aliphatic carbon show a smaller sensitivity (m) to changes in Y than those for the parent solvolysis reaction of tert-butyl chloride (for which m = 1 by definition). A second term was added ( N) to account for the effect of changes in solvent nucleophilicity on obsd that result from transition state stabilization by a nucleophilic interaction between solvent and substrate. It was first assumed that there is no significant stabilization of the transition state for solvolysis of tert-butyl chloride from such a nucleophilic interaction. However, a close examination of extensive rate data revealed, in some cases, a correlation between rate constants for solvolysis of fert-butyl derivatives and solvent nucleophicity. " ... 

Use of other methods has contributed further to the emerging picture of solvolysis of most secondary systems as being solvent-assisted. For example, the solvolysis rate acceleration on substituting a-hydrogen by CH3 in 2-adamantyl bromide is 107 5, much larger than that found for other secondary—tertiary pairs such as isopropyl-/-butyl. In molecules less hindered than 2-adamantyl, the secondary substrate is accelerated by nucleophilic attack of solvent.100 Rate accelerations and product distributions found on adding azide ion to solvolysis mixtures (Problem 4) also provide confirmatory evidence for these conclu-... 

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). 

P. E. Dietze, Nucleophilic Substitution and Solvolysis of Simple Secondary Carbon Substrates, in Advances in Carbocation Chemistry (J. M. Coxon, Ed.) 1995, 2, JAI, Greenwich, CT. 

Other evidence for ion pair return is less relevant to solvolyses of simple secondary substrates. It is known that during solvolyses of certain optically active substrates racemization occurs more rapidly than solvolysis, but it is not known whether the ion-pair intermediates undergoing racemization are the same as those undergoing solvolysis (Hammett, 1970a). Such behaviour is usually observed in solvolyses where neighbouring group participation occurs and the intermediates are probably more stable than those from simple secondary solvolyses. As the stabilities of the intermediates increase, there appears to be a general trend towards formation of more dissociated species,4 and thus the relevance of these results is questionable. 

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. 

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... 

The solvolysis of short-chain substrates (PNPA 3, NABA 6 NABS 3, etc.), when catalyzed by imidazole-containing homopolymers, usually follows the second-order kinetics. This implies that secondary-valence-force attractions, if operating, are not sufficient to cause substrate binding to a kinetically observable extent. The macro-molecule-substrate complexation, once proposed for the polyvinylimidazoIe-NABS system, (54) was shown to be an artifact caused by slow deacylation (55). 

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