Substitution, electrophilic partitioning effect

In this case a large isotope effect would be expected. If, however, k2 [B] k u then Equation 7.71 cannot be simplified, and the magnitude of k2 will affect the overall rate albeit in a less than linear way. Then, even if k2 > ku some isotope effect should be observed. The small isotope effect of Melander s experiments make it appear that the first step is slower than the second, but that k 1 competes favorably with k2. When the second step becomes kinetically important in spite of the first step being the slow step, we have an example of the partitioning effect— so-called because the kinetic significance of the second step arises from the way in which the intermediate partitions itself. Since 1950 a very large number of electrophilic substitutions have been examined for isotope effects in the absence of special circumstances (see below), the isotope effects found are usually very small.158... 

Ynenol lactones are also proposed to inactivate serine proteases irreversibly by alkylation of the active site histidine. Acylation of elastase by ynenol lactones produces an electrophilic allenone intermediate (Fig. 51) which covalently modifies and inactivates the enzyme with a partition ratio of 1.7 (Copp et al., 1987). Direct addition of the allenone carboxylic acid is without effect, demonstrating that the inactivator must be tethered in the active site to allow reaction with the enzyme. Substitution a to the lactone carbonyl is required for loss of activity, whereas the rate of inactivation is decreased by substitution at the acetylene terminus, suggesting that allene formation is slowed or that nucleophilic attack on the allene is hindered. 

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