Nucleophilic aromatic isotope effects

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

An S Ar (nucleophilic substitution at aromatic carbon atom) mechanism has been proposed for these reactions. Both nonenzymatic and enzymatic reactions that proceed via this mechanism typically exhibit inverse solvent kinetic isotope effects. This observation is in agreement with the example above since the thiolate form of glutathione plays the role of the nucleophile role in dehalogenation reactions. Thus values of solvent kinetic isotope effects obtained for the C13S mutant, which catalyzes only the initial steps of these reactions, do not agree with this mechanism. Rather, the observed normal solvent isotope effect supports a mechanism in which step(s) that have either no solvent kinetic isotope effect at all, or an inverse effect, and which occur after the elimination step, are kinetically significant and diminish the observed solvent kinetic isotope effect. 

Base-catalysed cyclization of proximate diacetyl aromatics [e.g. o-diaccty I benzene (36)] gives the corresponding enone (37). Relative rates, activation parameters, and isotope effects are reported for (36), and also for 1,8-diacetylnaphthalene, 4,5-diacetylphenanthrene, and 2,2/-diacetylbiphenyl, in aqueous DMSO.61 Reaction proceeds via enolate formation (rate determining for the latter three substrates), followed by intramolecular nucleophilic attack [rate determining for (36)], and finally dehydration. 

Studies of relative rates, activation parameters, kinetic isotope, and solvent isotope effects, and correlation of rates with an acidity function, have elucidated the mechanisms of cyclization of diacetyl aromatics (23-26) promoted by tetramethyl-ammonium hydroxide in DMSO.32 Rate-determining base-catalysed enolate anion formation from (24-26) is followed by relatively rigid intramolecular nucleophilic attack and dehydration whereas the cyclization step is rate determining for (23). 

But in nucleophilic aromatic substitution, we are dealing with displacement, not of hydrogen, but of elements like the haiogens as was discussed in connection with dehydrohalogenation, any isotope effects would be small, and hard to measure. 

At high pH, both oc-and p-NeuNAcOAr liberate ArO by a base-catalysed process which, however, shows only a weak dependence on the of ArOH P K —0.2), is not subject to a primary deuterium kinetic isotope effect at C3, and does not result from nucleophilic attack on the aromatic ring, as shown by 0 labelling. A possible, though far from proven, mechanism, is that of Figure 3.26. 

Obtaining both an isotope effect, k /k, and an element effect, k fk, are the experimental evidence that the C-H and C-X bonds are breaking in the transition structure. Since measurement of heavy atom isotope effects requires special instrumentation, the element effect has taken the place of heavy atom isotope effects in most investigations. The element effect was first proposed by Bunnett in a 1957 paper dealing with the nucleophilic substitution reactions of activated aromatic compounds [27], and later applied to dehydrohalogenation mechanisms by Bartsch and Burmett [28]. The lack of any incorporation of deuterium prior to elimination has also been used as experimental evidence favoring the concerted mechanism [29]. The stereochemistry should be a trans-elimination. 

There is a group of nucleophilic aromatic substitutions to which the hydrogen isotope effect technique can be applied, namely those with... 

Small hydrogen isotope effects have been found in a nucleophilic substitution of an aromatic heterocycle, the reaction of cyanuric chloride with aniline-N,N-d2 in benzene solution (Zollinger, 1961a). As the effects are small (5%), it is difficult to draw definite mechanistic conclusions. The reactions of cyanuric chloride and other halogenated triazine derivatives are subject to bifunctional catalysis (e.g. by carboxylic acids and by a -pyridone) and to catalysis by monofunctional bases like pyridine (Bitter and Zollinger, 1961). Reinheimer et al. (1962) measured the solvent isotope effect in the hydrolysis of 2-chloro-5-nitro-pyridine (A h,o/ d.o = 2 36). The result makes it probable, but... 

Stabilization of cationic intermediates by conjugation with an aromatic ring, as in the 1-phenylethyl system, leads to nucleophilic substitution with diminished stereospecificity. A thorough analysis of stereochemical, kinetic, and isotope effect data on solvolysis reactions of 1-phenylethyl chloride has been carried out. For the ion-pair equilibria... 

The role of the metal ion in ester hydrolysis catalysed by CPA has been examined with both Zn +- and Co +-substituted enzymes. When the terminal carboxyl of the substrate is electrostatically linked to argenine-145 and the aromatic side-chain lies in a hydrophobic pocket, the only residues close enough to the substrate to enter catalysis are glutamate-270, tyrosine-248, the metal ion, and its associated water. Low-temperature studies aid the elucidation of the mechanism. Between - 25 and - 45 °C in ethylene glycol-water mixtures two kinetically discrete processes are detected, the slower of which corresponds to the catalytic rate constant. The faster reaction is interpreted as deacylation of a mixed anhydride acyl-enzyme intermediate formed by nucleophilic attack by glutamate-270 on the substrate (Scheme 6). Differences in the acidity dependences of the catalytic rate constant with the metal ions Zn + (p STa 6.1) and Co +-(pATa 4.9) suggest that ionization of the metal-bound water molecule occurs and is involved in the decay of the anhydride. The catalytic rate constant shows an isotope effect in DgO. 

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