Nucleophilic constant stereochemistry

The points that we have emphasized in this brief overview of the S l and 8 2 mechanisms are kinetics and stereochemistry. These features of a reaction provide important evidence for ascertaining whether a particular nucleophilic substitution follows an ionization or a direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the Sj l mechanism and those exhibiting second-order kinetics react by the 8 2 mechanism. Many nucleophilic substitutions are carried out under conditions in which the nucleophile is present in large excess. When this is the case, the concentration of the nucleophile is essentially constant during die reaction and the observed kinetics become pseudo-first-order. This is true, for example, when the solvent is the nucleophile (solvolysis). In this case, the kinetics of the reaction provide no evidence as to whether the 8 1 or 8 2 mechanism operates. 

Figure 6.52 Mechanistic possibilities for transfer of a monophosphate, (a) 5 1 (P) involving a solvent-equilibrated metaphosphate intermediate. Protonation states are not shown, but different fonts for the phosphorus oxygens, representing different oxygen isotopes, indicate stereochemistry. (b) Canonical structures for metaphosphate and alkyl phosphate dianion, (c) 5n2(P) involving an intermediate which can pseudorotate, (d) Exploded 5Nl(P)-like >Sn2(P) transition states, and cartoon of calculated movements of phosphorus and non-bridge oxygens during phosphoryl transfer through such a transition state, where the leaving to nucleophile atom distance is constant.

Even so a Bronsted coefficient of 0.66 would account for the rate constant ratio. Both of these values fall within the range of Bronsted coefficients typically observed for general-acid catalysis. An acid with a pK of 6.9 is largely protonated at pH 5.1 and no corrections are required. From these considerations it is likely that the stereochemistry of the helix favors nucleophilic catalysis by the His residue with the highest number in the sequence and general-acid catalysis by the residue with the lowest number. 

When substitution occurs by an Sn2 mechanism, the nucleophile directly attacks the substrate, with the angle of approach being 180" to the C-L bond. This is called "backside attack," and the reaction proceeds with inversion of stereochemistry, the so-called "Walden inversion." The C-L bond is being broken concurrently with the formation of the C-Nu bond, so both the substrate, R-L, and the nucleophile are involved in the transition state of the rate-determining step. Reactions in which two reactants are involved in the transition state of the rate-determining step are termed bimolecular, and the rate of such processes depends on the concentration of the substrate and the nucleophile, as shown in Equation 14.5, where k2 is the second-order rate constant. 

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