Acidity, deuterium isotope effect

Another circumstance which could change the most commonly observed characteristics of the two-stage process of substitution has already been mentioned it is that in which the step in which the proton is lost is retarded because of a low concentration of base. Such an effect has not been observed in aromatic nitration ( 6.2.2), but it is interesting to note that it occurs in A -nitration. The A -nitration of A -methyl-2,4,6-trinitroaniline does not show a deuterium isotope effect in dilute sulphuric acid but does so in more concentrated solutions (> 60 % sulphuric acid kjj/kjj = 4 8). ... 

For this type of reaction the value of the solvent deuterium isotope effect is often a conclusive argument for the proposed mechanism 16). Rate measurements of 1 in acetic acid-acetate buffers in light and heavy water resulted in an isotope effect ktiiO lkozo of 2.5, and A oac/ doac of 9. A ratedetermining proton transfer to the /3-carbon atom of the enamine has been proposed and accounts for the experimental results I6-18 Eq. (5). 

The secondary a-deuterium isotope effects on azo coupling reactions are small, i.e., km/kiv is very close to unity. For the reaction of the 4-nitrobenzenediazonium ion with the trianion of l-D-2-naphthol-6,8-disulfonic acid catalyzed by pyridine, km/kiv = 1.06 0.04 (Hanna et al., 1974). 

It is claimed that the limiting value of k bs, 2.81 x 10" sec-1, represents the rate coefficient for the rearrangement reaction above (k,). The ring deuterium isotope effect kH kD was re-determined for this individual rate coefficient for rearrangement by finding the limiting value in the presence of added N-methylaniline and was found to be 2.4 at two different acidities, as compared with 1.7 for the ratio of the observed composite rate coefficients, as expected, since no isotope effect would be predicted for the de-nitrosation step. 

For each catalyst, the mechanism for one direction is the exact reverse of the other, by the principle of microscopic reversibility. As expected from mechanisms in which the C—H bond is broken in the rate-determining step, substrates of the type RCD2COR show deuterium isotope effects (of 5) in both the basic- and the acid -catalyzed processes. 

The rates of hydration of substituted phenylpropiolic acids give a rho of —4.77 when plotted against a, comparable to Ihe acid-catalyzed isomerization of czs-cinnamic acid, with a rho value of —4.3. The solvent deuterium isotope effects are 3.7-S.2 for the isomerization of cinnamic acids at... 

A second reason for the larger isotope effect observed by Jones and Maness (140) might be that in the less polar acetic acid solvent, there might be a small degree of E2 elimination (with solvent acting as base) superimposed on the dominant Sn 1 mechanism. Such an elimination would involve a primary kinetic deuterium isotope effect with a kn/ko s 2 to 6, and hence even a 1 to 5% contribution from such a pathway would have a significant effect on the experimentally observed kinetic isotope effect. 

The acid catalysed denitrosation of N-nitrosamides is subject to a substantial solvent deuterium isotope effect [k (H)/k (D)... 

This all seemed very reasonable at the time, but subsequent work was not consistent with it. A small but measurable amount of 180 exchange was reported for some amides in reasonably concentrated HC1 media,277,278 and for at least one amide the amount of exchange decreased with increasing acidity,277 which is the opposite of what would be expected with the Scheme 14 one-water-molecule mechanism taking over from the equation (74) three-water-molecule mechanism as the acidity increased. Also, the solvent deuterium isotope effect was found to be close to unity for at least one amide,278 a result that has since been confirmed,279 which is not what would be expected on the basis of either a three- or a one-water-molecule process.280 Because of this it was decided to reexamine the lactam hydrolysis data subsequent to the publication of the excess acidity analysis of the H NMR results for these,268 a new study appeared with rate constant data for four of these molecules in aqueous H2S04 media obtained by UV spectroscopy at several temperatures,281 and this was included too.282... 

The observation of a primary solvent deuterium isotope effect (kH/fa>) = 2-4 on the specific acid-catalyzed hydrolysis of vinyl ethers provides evidence for reaction by rate-determining protonation of the alkene.69 Values of kHikD 1 are expected if alkene hydration proceeds by rate-determining addition of solvent to an oxocarbenium ion intermediate, since there is no motion of a solvent hydron at the transition state for this step. However, in the latter case, determination of the solvent isotope effect on the reaction of the fully protonated substrate is complicated by the competing exchange of deuterium from solvent into substrate (see above). 

The formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common in both nitration and nitrosation processes. However, the contrasting reactivity trend in various nitrosation reactions with NO + (as well as the observation of substantial kinetic deuterium isotope effects) is ascribed to a rate-limiting deprotonation of the reversibly formed Wheland intermediate. In the case of aromatic nitration with NO, deprotonation is fast and occurs with no kinetic (deuterium) isotope effect. However, the nitrosoarenes (unlike their nitro counterparts) are excellent electron donors as judged by their low oxidation potentials as compared to parent arene.246 As a result, nitrosoarenes are also much better Bronsted bases249 than the corresponding nitro derivatives, and this marked distinction readily accounts for the large differentiation in the deprotonation rates of their respective conjugate acids (i.e., Wheland intermediates). 

Tetrahedral intermediates, derived from carboxylic acids, spectroscopic detection and the investigation of their properties, 21, 37 Topochemical phenomena in solid-state chemistry, 15, 63 Transition state structure, crystallographic approaches to, 29, 87 Transition state structure, in solution, effective charge and, 27, 1 Transition state structure, secondary deuterium isotope effects and, 31, 143 Transition states, structure in solution, cross-interaction constants and, 27, 57 Transition states, the stabilization of by cyclodextrins and other catalysts, 29, 1 Transition states, theory revisited, 28, 139... 

The authors have also synthesized134 fatty acids labelled with deuterium and carbon-11 in order to investigate if kinetic isotope effects related to fatty acid metabolism can be observed in vivo by pet133,135-137. In vitro, the large kinetic deuterium isotope effects are observed in the oxidation of deuteriated aliphatic carboxylic acids with alkaline permanganate and manganate135-139. 

The observed normal isotope effect of 1.9 provides further evidence supporting the role of Asp55 as the general base. Namely, a normal isotope effect of 1.9 is most consistent with general base catalysis by an amino acid side chain, as inverse isotope effects are commonly observed when a zinc-bound water molecule, or hydroxide, is the attacking nucleophile. For example, the zinc-containing enzymes AMP deaminase [111], thermolysin [112], stromelysin [113], and a desuccinylase [114] are each believed to utilize a zinc-bound water as the nucleophile, and all of these reactions are characterized by an inverse deuterium isotope effect. This inverse isotope effect is thought to result from a dominant... 

Ab initio MO calculations have been carried out for two carbocation-generating reactions the 6 nI reaction of protonated 1-phenylethanol (H2O leaving group) and the acid-catalysed hydration of styrene. Optimizations were done at the MP2/6-31G level. The 6 nI transition state lies half way between the reactant and the product with respect to the bond lengths, charge distribution, and secondary deuterium isotope effects. 

It was shown that the patterns of the relative rates of reaction of DPC and DPC with alcohols are essentially identical and followed the relative acidity of the alcohols (MeOH > /-PrOH > f-BuOH) and showed a kinetic deuterium isotope effect on reaction with the OH bond (Table 9.13). These results indicate that DPC attacks the O—H bond rather than the C—H bond of the alcohol. If the C—H bonds of the alcohol were attacked by DPC, as in the ground triplet state reaction, then one would expect 2-propanol would react faster than methanol. Lack of any dis-cernable quenching of DPC by diethyl ether and THF indicates that DPC ... 

---