Preassociation mechanism, 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... 

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.

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). 

Bimolecular preassociation mechanism with water as a nucleophile. 

X 10 ° s for 75f. These ions are predicted to react with solvent H2O too rapidly for efficient trapping by non-solvent nucleophiles, so other inefficient trapping mechanisms such as preassociation can compete. The transition... 

To make the task more manageable this chapter will focus specifically on the interaction between the nucleophile and a double bond and not consider in any depth subsequent steps. We will also only briefly consider reactions in which there is a preassociation or complexation of the double bond with a Lewis acid prior to nucleophilic attack. Finally we shall concentrate on conventional nucleophilic attack and not discuss mechanisms involving single electron processes. In Section II we shall examine the types of double bonds that undergo nucleophilic attack, in particular examining relative reactivity, where available, and models for explaining this order. In Section III we shall review the orbital interactions that control the approach of a nucleophile to the double bond and the associated geometrical constraints. Then in Section IV we shall consider the implications of these constraints on selective reactions. 

Bourne and Williams (1983) reached a similar conclusion. They analysed the reaction of phosphorylated isoquinoline with a series of pyridines whose conjugate acids have pAf -values that straddle that of isoquinoline. The logarithms of the observed rate constants show a linear dependence on of the nucleophile, and therefore free metaphosphate is likely to be excluded as a reaction intermediate (unless there is no change in slope about the equal-pAf point). A straight line is found rather than the curve that would be found for a stepwise mechanism with a change in rate-determining step. The authors argue that a preassociation-concerted mechanism best accounts for the data. Operationally this should be equivalent to a concerted reaction. However, it is difficult to tell if a small amount of curvature exists, and more extensive studies on the same problem have addressed the question in further detail. 

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