Isotopes nucleophilic aromatic substitution

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. 

Scheme 16.2. In a classic experiment, Roberts et al. demonstrated the involvement of 4 in the nucleophilic aromatic substitution by isotopic labeling experiments. The product distribution can only be explained by the assumption of a symmetric intermediate.

After a new (and unusual) mechanism, such as the benzyne mechanism for nucleophilic aromatic substitution, is proposed, experiments are usually designed to test that mechanism. A classic experiment supporting the benzyne mechanism used a radioactive carbon label. Examination of the mechanism shown in Figure 17.6 shows that the carbon bonded to the leaving chlorine and the carbon ortho to it become equivalent in the benzyne intermediate. Consider what would happen if the carbon bonded to the chlorine were a radioactive isotope of carbon (l4C) rather than the normal isotope of carbon (I2C). If we follow the position of the radioactive carbon label through the mechanism of Figure 17.6, we find that the label should be equally distributed between the carbon attached to the amino group in the product and the carbon ortho to it. 

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. 

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

Despite both intramolecular and intermolecular mechanisms for the Chapman rearrangement having been postulated [28], it is the intramolecular one that has been confirmed by crossover experiments and isotopic labeling studies [29]. It has also been observed that the rearrangement follows first-order kinetics involving a nucleophilic aromatic substitution step [30]. 

Four nucleophilic aromatic substitution reactions with amines have been studied for deuterium isotope effects. Hawthorne (81) found that the rates of reaction of o- and p- nitrochlorobenzene with piperidine in xylene are not altered by substitution of deuterium for hydrogen on the amino group of the nucleophile. Similarly, 2,4-dinitrochlorobenzene reacts at identical rates with -butylamine and with iV,iV-dideuterio-n-butylamine containing 0.75% ethanol (76). Under the conditions of the rate measurements the deuterated amine does not undergo exchange with either the chloroform or the ethanol present. Finally, the reaction of trichloro-s-triazene with aniline shows no isotope effect with AT,JV-dideuterioaniline in benzene as well as in benzene saturated with deuterium oxide (82). 

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. 

---