Nucleophilic addition isotope effects

However, measurements of substituent effects supported the hypothesis that the aryl cation is a key intermediate in dediazoniations, provided that they were interpreted in an appropriate way (Zollinger, 1973a Ehrenson et al., 1973 Swain et al., 1975 a). We will first consider the activation energy and then discuss the influence of substituents, as well as additional data concerning the aryl cation as a metastable intermediate (kinetic isotope effects, influence of water acitivity in hydroxy-de-di-azoniations). Finally, the cases of dediazoniation in which the rate of reaction is first-order with regard to the concentration of the nucleophile will be critically evaluated. 

Benzocyclobutene-l,2-dione (74) undergoes base-catalysed ring fission between the carbonyls to give 2-formy I benzoate (75). Rate constants, activation parameters, isotope effects, and substituent effects have been measured in water.107 Rapid reversible addition of hydroxide to one carbonyl is followed by intramolecular nucleophilic attack on die otiier, giving a resonance-stabilized carbanionic intermediate (76a)-o-(76b). 

The results in Table 3 were explained as shown in Scheme 4. From the fact that no kinetic isotope effect was observed in the reaction of phenyl-substituted disilenes with alcohols (Table 1), it is assumed that the addition reactions of alcohols to phenyltrimethyl-disilene proceed by an initial attack of the alcoholic oxygen on silicon (nucleophilic attack at silicon), followed by fast proton transfer via a four-membered transition state. As shown in Scheme 4, the regioselectivity is explained in terms of the four-membered intermediate, where stabilization of the incipient silyl anion by the phenyl group is the major factor favoring the formation of 26 over 27. It is well known that a silyl anion is stabilized by aryl group(s)443. Thus, the product 26 predominates over 27. However, it should be mentioned that steric effects also favor attack at the less hindered SiMe2 end of the disilene, thus leading to 26. 

Kinetic isotope effect measurements support this interpretation. A small kinetic isotope effect (kR/kD = 0.71) is observed for p-methoxyphenol in agreement with a ratedetermining nucleophilic attack, while a large kinetic isotope effect (kR/kR = 5.27), observed for p-trifluoromethylphenol, strongly supports a mechanism in which a phenolic H (or D) is transferred to 39 in the rate-determining step. Unfortunately, 39 is a symmetric disilene so that diastereoselectivity could not be determined. It will be interesting to examine whether the diastereoselectivity will be effected by the change in the addition mechanism from electrophilic to nucleophilic. 

Recent developments in the asymmetric addition of aldehydes have been reviewed,206 as have asymmetric catalysis using metal complexes207 and nucleophile isotope effects 208... 

Application of the extended Grunwald-Winstein equation to solvolyses of propyl chloroformate, PrOCOCl, in a variety of pure and binary solvents indicated an addition-elimination pathway in the majority of the solvents but an ionization pathway in the solvents of highest ionizing power and lowest nucleophilicity. For methanolysis, a solvent deuterium isotope effect of 2.17 was compatible with the incorporation of general-base catalysis into the substitution process.21... 

Rates and product selectivities 5 = ([ester product]/[acid product]) x ([water]/ [alcohol solvent] were reported for solvolyses of chloroacetyl chloride at —10 °C and phenylacetyl chloride at 0 °C in EtOH- and MeOH-water mixtures. Additional kinetic data were reported for solvolyses in acetone-water, 2,2,2-trifluoroethanol (TFE)-water, and TFE-EtOH mixtures. Selectivities and solvent effects for chloroacetyl chloride, including the kinetic solvent isotope effect (KSIE) of 2.18 for MeOH, were similar to those for solvolyses of p-nilrobcnzoyl chloride rate constants in acetone-water were consistent with a third-order mechanism, and rates and products in EtOH-and MeOH-water mixtures could be explained quantitatively by competing third-order mechanisms in which one molecule of solvent (alcohol or water) acts as a nucleophile and another acts as a general base (an addition-elimination reaction channel) (29 R = Et, Me, H).23... 

As a mechanistic tool in the investigation of acid- or base-catalysed reactions in aqueous solution, the measurements in isotopically mixed solvents are most useful for reactions where a certain amount is already known about the mechanism. In particular, the study of mixed solvents is also a good deal more informative whenever it is possible to measure product isotope effects in addition to rate isotope effects. In such cases (and A-Sb2 reactions spring to mind as a good example) solvent isotope effect studies can add considerably to the detailed picture of a transition state. The phenomena are as yet less suited to the ah initio assignment of reaction mechanism, such as the decision between weak nucleophilic participation of water in an acid-catalysed reaction and an A-l mechanism, when no information beyond the kn-n relation is available. For these reasons it is likely that mechanistic investigation by this method will increasingly be directed towards systems where both rate and product isotope effects are obtainable. 

In contrast, reaction of electron acceptor-substituted phenols exhibits p = +1.72, indicating the development of negative charge at the phenolic oxygen in the rate-determining step for reaction of relatively acidic, weakly nucleophilic phenols with 110, and the addition of 112f exhibits a large primary deuterium kinetic isotope effect of k /kv = 5.3. This is consistent with the electrophilic addition mechanism of equation 85, in which full or partial protonation at silicon precedes nucleophilic attack. 

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