Borderline reactions, nucleophilic substitution mechanisms

Sneen et al. formulated an intermediate-mechanism theory. The formulation is in fact very broad and applies not only to borderline behavior but to all nucleophilic substitutions at a saturated carbon. According to Sneen, all SnI and Sn2 reactions can be accommodated by one basic mechanism (the ion-pair mechanism). The substrate first ionizes to an intermediate ion pair that is then converted to products ... 

Students of reaction mechanism will recognize intuitively that the difference between the narrow and broad borderline regions observed for nucleophilic substitution of azide ion at secondary and tertiary carbon (Fig. 2.2) is due to the greater steric hindrance to bimolecular nucleophilic substitution at the tertiary carbon. This leads to a large difference in the effects of an a-Me group on (s ) for the stepwise solvolysis and s ) for concerted bimolecular nucleophilic... 

The yield of the nucleophilic substitution product from the stepwise preassociation mechanism k[ = k. Scheme 2.4) is small, because of the low concentration of the preassociation complex (Xas 0.7 M for the reaction of X-2-Y). Formally, the stepwise preassociation reaction is kinetically bimolecular, because both the nucleophile and the substrate are present in the rate-determining step ( j). In fact, these reactions are borderline between S l and Sn2 because the kinetic order with respect to the nucleophile cannot be rigorously determined. A small rate increase may be due to either formation of nucleophile adduct by bimolecular nucleophilic substitution or a positive specific salt effect, whUe a formally bhnole-cular reaction may appear unimolecular due to an offsetting negative specific salt effect on the reaction rate. 

The change from a stepwise preassociation mechanism through a triple ion intermediate to an uncoupled concerted reaction occurs as the triple ion becomes too unstable to exist in an energy well for the time of a bond vibration ( 10 s). The borderline between these two reaction mechanisms is poorly marked, and there are no clear experimental protocols for its detection. These two reaction mechanisms cannot be distinguished by experiments designed to characterize their transition states, which lie at essentially the same position in the inner upper right hand corner of Figure 2.3. Only low yields of the nucleophilic substitution product are obtained from both stepwise preassociation and uncoupled concerted reactions, because for formation of the preassociation complex in water is small... 

Nucleophilic Substitution at Benzyl Derivatives. The sharp break from a stepwise to a concerted mechanism that is observed for nucleophilic substitution of azide ion at X-l-Y (Figs. 2.2 and 2.5) is blurred for nucleophilic substitution at the primary 4-methoxybenzyl derivatives (4-MeO,H)-3-Y. For example, the secondary substrate (4-MeO)-l-Cl reacts exclusively by a stepwise mechanism through the liberated carbocation intermediate (4-MeO)-T, which shows a moderately large selectivity toward azide ion ( az/ s = 100 in 50 50 (v/v) water/ trifluoroethanol). The removal of an a-Me group from (4-MeO)-l-Cl to give (4-MeO,H)-3-Cl increases the barrier to ionization of the substrate in the stepwise reaction relative to that for the concerted bimolecular substitution of azide ion. The result is that both of these mechanisms are observed concurrently for nucleophilic substitution of azide ion at (4-MeO,H)-3-Cl in water/acetone solvents. These concurrent stepwise and concerted nucleophilic substitution reactions of azide ion with (4-MeO,H)-3-Cl show that there is no sharp borderline between mechanisms for substitution at primary benzylic carbon, but instead a region of overlap where both mechanisms are observed. 

The essential features of the mechanism for aliphatic nucleophilic substitution at tertiary carbon were established in studies by Hughes and Ingold." ° However, as chemists probed more deeply, the problems associated with the characterization of borderline reaction mechanisms were encountered, and controversy remains to this day about whether these problems have been entirely solved." What is generally accepted is that ferf-butyl derivatives undergo borderline solvolysis reactions through a ferf-butyl carbocation intermediate that is too unstable to diffuse freely through nucleophilic solvents such as methanol and water. The borderline nature of substitution reactions at tertiary carbon is exemplihed by the following observations. 

Generally, only a single stepwise or concerted pathway for aliphatic nucleophihc substitution is detected by experiment because of the very different activation barriers for formation of the respective reaction transition states for these reactions. The description of the borderline between stepwise and concerted nucleophilic substitution reactions presented in this chapter has been obtained through a search for those rare substrates that show comparable barriers to these two reactions and through the characterization of the barrier for nucleophile addition to the putative carbocation intermediate of the stepwise reaction in the region of this change in mechanism. 

Some nucleophilic substitution reactions that seem to involve a borderline mechanism actually do not. Thus, one of the principal indications that a borderline mechanism is taking place has been the finding of partial racemization and partial inversion. However, Weiner and Sneen have demonstrated that this type of stereochemical behavior is quite consistent with a strictly Sn2 process. These workers studied the reaction of optically active 2-octyl brosylate in 75% aqueous dioxane, under which conditions inverted 2-octanol was obtained in 77% optical purity. When... 

Studies of the stereochemistry are a powerful tool for investigation of nucleophilic substitution reactions. Direct displacement reactions by the Sjv2(lim) mechanism are expected to result in complete inversion of configuration. The stereochemical outcome of the ionization mechanism is less predictable, because it depends on whether reaction occurs via an ion pair intermediate or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of ion pair recombination. 

Since ion pairs are undoubtedly important species, the question has arisen as to whether they might be intermediates in all nucleophilic substitution processes. R. A. Sneen and H. M. Robbins suggested that ion pairs might not only be involved in SnI and borderline processes but also in displacements exhibiting the stereochemical and kinetic characteristics of the Sn2 process. They suggested the scheme shown below, in which SOH is a hydroxylic solvent and Nu" is a nucleophilic anion. In this mechanism, reactions with Sn2 characteristics are postulated to occur by nucleophilic attack on the intimate ion pair. 

Szele and Zollinger (1978 b) have found that homolytic dediazoniation is favored by an increase in the nucleophilicity of the solvent and by an increase in the elec-trophilicity of the P-nitrogen atom of the arenediazonium ion. In Table 8-2 are listed the products of dediazoniation in various solvents that have been investigated in detail. Products obtained from heterolytic and homolytic intermediates are denoted by C (cationic) and R (radical) respectively for three typical substituted benzenediazonium salts and the unsubstituted salt. A borderline case is dediazoniation in DMSO, where the 4-nitrobenzenediazonium ion follows a homolytic mechanism, but the benzenediazonium ion decomposes heterolytically, as shown by product analyses by Kuokkanen (1989) the homolytic process has an activation volume AF = + (6.4 0.4) xlO-3 m-1, whereas for the heterolytic reaction AF = +(10.4 0.4) x 10 3 m-1. Both values are similar to the corresponding activation volumes found earlier in methanol (Kuokkanen, 1984) and in water (Ishida et al., 1970). 

Reaction of a-haloketone with a nucleophile can give carbonyl addition, direct substitution, and proton abstraction. DFT calculations suggest that the reaction of hydroxide with a-bromoacetophenone (PhCOCH2Br) is a borderline case, with an addition/substitution TS, where hydroxide interacts with/bridges the two carbons. Such a TS could serve for two mechanisms, with path bifurcation after the TS, leading to the respective hydrate anion [Ph-C(0H)(0 )CH2Br] and substitution products... 

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