Preassociation mechanisms

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... 

Reactions of nitrenium ions with lifetimes in aqueous solution ns. It is clear from the work presented to date that these species react predominately by ion-pair or preassociation mechanisms, but the detailed processes are far from clear. The possible transition to a true bimolecular substitution mechanism (Sn2) has also not been systematically investigated. 

The preassociation mechanism is more efficient than the trapping mechanism because it generates an intermediate which immediately reacts by an ultrafast proton transfer (in the pre-association complex, Int) and thus avoids the diffusion-controlled step bringing the catalyst and intermediate together. This mechanism is sometimes called a spectator mechanism because, although the catalyst is present in the transition structure, it is not undergoing any transformation [10]. 

The descending nucleophile selectivity (7left-hand limb of Fig. 1 for stepwise solvolysis of R-X is due to the increase in ks (s-1), with decreasing stability of the carbocation intermediate, relative to the constant value of /taz (M-1 s-1) for the diffusion-limited addition of azide anion. The lifetime for the carbocation intermediate R+ eventually becomes so short that essentially no azide ion adduct forms by diffusion-controlled trapping, because addition of solvent to R+ occurs faster than escape of the carbocation from the solvent cage followed by addition of azide ion (k s > k-d). Now, the nucleophile adduct must form through a preassociation mechanism, where the azide anion comes together in an association... 

Fig. 1 A hypothetical plot of azide ion selectivity fcaz/fcs (M-1) against the reactivity of the carbocation intermediate of solvolysis of R-X in aqueous solution (Scheme 4). The descending limb on the left hand side of this plot is for reactions where the value of ks (s-1) is increasing relative to the constant value of k (M-1 s-1) for diffusion-limited addition of azide ion to the carbocation. The constant nucleophile selectivity is for reaction of R-X by a preassociation mechanism.

Rebek and his co-workers have shown that replication - autocatalysis based on molecular recognition - best accommodates the facts observed in the reaction of 42 with 43, and that under the published conditions 44 is responsible for the autocatalysis. The results indicated template-catalyzed replication as the source of autocatalysis, where recognition surfaces and functional groups interact to form a productive termolecular complex. The mechanism demands that catalysis would be absent with esters that lack hydrogen-bonding sites. One complication of this system is that the initial product of this bimolecular preassociative mechanism is postulated to be a cw-amide, which isomerized to the frani-amide, the active form of template. This appears to be one major background reaction for product formation (Scheme 14). 

The nucleophilic substitution reactions of anilines with ero-2-norbomyl arenesulfonates, 2, present an interesting example of the preassociation mechanism55 (Scheme 1). The rate is faster with 2-exo (k2 = 15.9 x 10 4 and 3.24 x 10-5 M 1 s 1 when X = Z = H in MeOH and MeCN at 60.0 °C, respectively) than with 2-endo (k2 = 0.552 x 10 5 M 1 s 1 with X = Z = H in MeOH at 60.0 °C). These reactions are characterized by a large pz (1.8 and 1.2 for 2-exo and 2-endo) coupled with a small magnitude of px (—0.21 and —0.15 for 2-exo and 2-endo). The pz values for the aniline reactions are even larger than those for the SY 1 solvolysis in MeOH (pz =1.5 and 1.0 for solvolysis of 2-exo and 2-endo). Thus the abnormal substituent effect in the anilinolysis of 2 can only be accounted for by the preassociation mechanism of Scheme 1. The upper route is the normal S/v 1 pathway, and the lower route is the preassociation pathway. The preassociation step, Xass, and association of the Nu to the ion pairs, kn. occur in a diffusion limited or fast process and k is the rate-limiting step. This mechanism leads to second-order kinetics and therefore is an SY/2 process, but structural effects on rates are very similar to those of S l reactions, since the R+ Z pair consists essentially of the two free ions. 

Fig. 8 Potential mechanisms for hydrolysis of phosphomonoester monoanions. In mechanism (a), proton transfer from the phosphoryl group to the ester oxygen (probably via the intermediacy of a water molecule) yields an anionic zwitterion intermediate. This may react in either concerted fashion (upper pathway) or via a discrete metaphosphate intermediate in a preassociative mechanism (bottom pathway). Mechanism (b) denotes proton transfer concerted with P-O(R) bond fission. As with (a), such a mechanism could either occur with concerted phosphoryl transfer to the nucleophile (upper pathway) or via a discrete metaphosphate intermediate in a preassociative mechanism (bottom pathway).

Thus, even though free metaphosphate anion cannot be considered a mechanistically significant intermediate in enzyme-catalyzed phosphate monoester ester hydrolysis, since it is unlikely that an acceptor nucleophile will not be present to participate in a preassociative mechanism, it can exist in solution under appropriate solvent conditions when an acceptor nucleophile is unavailable. 

Reactions of phosphate monoester dianions and of phosphorylated pyridines with water and other nucleophiles proceed through a mechanism that shows many of the characteristics expected for reaction through an intermediate metaphosphate monoanion, and several investigators (3-5) have suggested that these and related reactions proceed through such an intermediate. However, recent work has shown that metaphosphate, if it is formed, has too short a lifetime in several hydroxylic solvents to diffuse through the solvent before reaction, so that the reaction must occur by a stepwise or concerted preassociation mechanism. Methanolysis of the 2,4-dinitrophenyl phosphate dianion occurs with inversion, for example (6). 

Fig. 10. Free energy diagram illustrating how a preassociation mechanism (lower curve) provides the lowest energy pathway for a reversible carboligation reaction when the intermediate carbanion reacts more rapidly with BH (k -i) than with the carbonyl function (it a). [From Ref. (229), with permission.)...

The rate enhancement obtainable by preassociation compared with trapping is given by the ratio of the rate of breakdown of the intermediate I to generate reactants to the rate of dissociation of the intermediate and catalyst I.C. (Fig. 3). The maximum lowering of the free energy of activation obtainable is the activation energy for diffusion of apart of the catalyst and intermediate i.e. ca. 15 kJ/mole, a rate enhancement of ca. 400. There can be no rate advantage from a preassociation mechanism when the proton transfer is thermodynamically unfavourable. 

Bimolecular preassociation mechanism with water as a nucleophile. 

Transition states for bond formation and breakage mirror each other. Such a condition requires that diffusion apart of the complex and either group is slower than bond formation with either group. If one group could depart then so could the other, which is not the case. This is an enforced preassociation mechanism. The only alternative to this mechanism that is consistent with the data would arise if the intermediate had too short a lifetime to exist and the reaction was concerted, proceeding via a penta-covalent intermediate or transition state. 

Table 12.5 gives data for the second-order region for anation of [Ni(H20)6], which is hypothesized to occur via a preassociation mechanism. The second-order rate constant, k2Ki, is the product of the ion-pair equilibrium constant, Ki, and the rate constant, k2 (Section 12.3.4) ... 

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