Kinetic isotope effect, mechanism

Berti PJ, Tanaka KSE (2002) Transition state analysis using multiple kinetic isotope effects mechanisms of enzymatic and non-enzymatic glycoside hydrolysis and transfer. Adv. Phys. Org. Chem. 37 239-314... 

Transition State Analysis Using Multiple Kinetic Isotope Effects Mechanisms of Enzymatic and Non-enzymatic Glycoside Hydrolysis and Transfer... 

It is clear, then, that the measurement of primary kinetic isotope effects will not give a wholly unambiguous clue to mechanism in the absence of other evidence. Nevertheless, the absence of a kinetic isotope effect is most easily understood in terms of the /S 2 mechanism... 

Melander first sought for a kinetic isotope effect in aromatic nitration he nitrated tritiobenzene, and several other compounds, in mixed acid and found the tritium to be replaced at the same rate as protium (table 6.1). Whilst the result shows only that the hydrogen is not appreciably loosened in the transition state of the rate-determining step, it is most easily understood in terms of the S 2 mechanism with... 

The cases of pentamethylbenzene and anthracene reacting with nitronium tetrafluoroborate in sulpholan were mentioned above. Each compound forms a stable intermediate very rapidly, and the intermediate then decomposes slowly. It seems that here we have cases where the first stage of the two-step process is very rapid (reaction may even be occurring upon encounter), but the second stages are slow either because of steric factors or because of the feeble basicity of the solvent. The course of the subsequent slow decomposition of the intermediate from pentamethylbenzene is not yet fully understood, but it gives only a poor yield of pentamethylnitrobenzene. The intermediate from anthracene decomposes at a measurable speed to 9-nitroanthracene and the observations are compatible with a two-step mechanism in which k i k E and i[N02" ] > / i. There is a kinetic isotope effect (table 6.1), its value for the reaction in acetonitrile being near to the... 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

The details of proton-transfer processes can also be probed by examination of solvent isotope effects, for example, by comparing the rates of a reaction in H2O versus D2O. The solvent isotope effect can be either normal or inverse, depending on the nature of the proton-transfer process in the reaction mechanism. D3O+ is a stronger acid than H3O+. As a result, reactants in D2O solution are somewhat more extensively protonated than in H2O at identical acid concentration. A reaction that involves a rapid equilibrium protonation will proceed faster in D2O than in H2O because of the higher concentration of the protonated reactant. On the other hand, if proton transfer is part of the rate-determining step, the reaction will be faster in H2O than in D2O because of the normal primary kinetic isotope effect of the type considered in Section 4.5. 

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

A substantial body of data, including reaction kinetics, isotope effects, and structure-reactivity relationships, has permitted a thorough understanding of the steps in aromatic nitration. As anticipated from the general mechanism for electrophilic substitution, there are three distinct steps ... 

When one of the ortho hydrogens is replaced by deuterium, the rate drops from 1.53 X 10 " s to 1.38 X lO s. What is the kinetic isotope effect The product from such a reaction contains 60% of the original deuterium. Give a mechanism for this reaction that is consistent with both the kinetic isotope effect and the deuterium retention data. 

Indicate mechanisms that would account for the formation of each product. Show how the isotopic substitution could cause a change in product composition. Does your mechanism predict that the isotopic substitution would give rise to a primary or secondary deuterium kinetic isotope effect Calculate the magnitude of the kinetic isotope effect from the data given. 

Consider a reactant molecule in which one atom is replaced by its isotope, for example, protium (H) by deuterium (D) or tritium (T), C by C, etc. The only change that has been made is in the mass of the nucleus, so that to a very good approximation the electronic structures of the two molecules are the same. This means that reaction will take place on the same potential energy surface for both molecules. Nevertheless, isotopic substitution can result in a rate change as a consequence of quantum effects. A rate change resulting from an isotopic substitution is called a kinetic isotope effect. Such effects can provide valuable insights into reaction mechanism. 

Despite its apparent simplicity, the PK pyrrole synthesis has retained its mystique since being discovered. Several investigations into the PK mechanism have been reported, including a gas phase study. Current evidence (intermediate isolation, kinetics, isotope effects) suggests the following (abbreviated) mechanism for the formation of pyrrole 13. However, the specific PK mechanism is often dependent on pH, solvent, and amine and dicarbonyl structure, especially with regard to the ringclosing step. 

A distinction between these four possibilities can be made on the basis of the kinetic isotope effect. There is no isotope effect in the arylation of deuterated or tritiated benzenoid compounds with dibenzoyl peroxide, thereby ruling out mechanisms in which a C5— bond is broken in the rate-determining step of the substitution. Paths (ii) and (iii,b) are therefore eliminated. In path (i) the first reaction, Eq. (6), is almost certain to be rate-determining, for the union of tw o radicals, Eq. (7), is a process of very low activation energy, while the abstraction in which a C—H bond is broken would require activation. More significant evidence against this path is that dimers, Arz, should result from it, yet they are never isolated. For instance, no 4,4 -dinitrobiphenyl is formed during the phenylation of... 

The mechanism proposed for the production of radicals from the N,N-dimethylaniline/BPO couple179,1 involves reaction of the aniline with BPO by a Sn-2 mechanism to produce an intermediate (44). This thermally decomposes to benzoyloxy radicals and an amine radical cation (46) both of which might, in principle, initiate polymerization (Scheme 3.29). Pryor and Hendrikson181 were able to distinguish this mechanism from a process involving single electron transfer through a study of the kinetic isotope effect. 

Important additional evidence for aryl cations as intermediates comes from primary nitrogen and secondary deuterium isotope effects, investigated by Loudon et al. (1973) and by Swain et al. (1975 b, 1975 c). The kinetic isotope effect kH/ki5 measured in the dediazoniation of C6H515N = N in 1% aqueous H2S04 at 25 °C is 1.038, close to the calculated value (1.040-1.045) expected for complete C-N bond cleavage in the transition state. It should be mentioned, however, that a partial or almost complete cleavage of the C — N bond, and therefore a nitrogen isotope effect, is also to be expected for an ANDN-like mechanism, but not for an AN + DN mechanism. 

Some diazonium couplings are subject to base catalysis and in these cases kinetic isotope effects are observed but since the rate of catalysed reaction is not linearly related to the base concentration (see p. 7), the SE3 mechanism is ruled out and the Se2 mechanism must operate, viz. 

Baechler and coworkers204, have also studied the kinetics of the thermal isomerization of allylic sulfoxides and suggested a dissociative free radical mechanism. This process, depicted in equation 58, would account for the positive activation entropy, dramatic rate acceleration upon substitution at the a-allylic position, and relative insensitivity to changes in solvent polarity. Such a homolytic dissociative recombination process is also compatible with a similar study by Kwart and Benko204b employing heavy-atom kinetic isotope effects. 

What concerns us here are three topics addressing the fates of bromonium ions in solution and details of the mechanism for the addition reaction. In what follows, we will discuss the x-ray structure of the world s only known stable bromonium ion, that of adamantylideneadamantane, (Ad-Ad, 1) and show that it is capable of an extremely rapid degenerate transfer of Br+ in solution to an acceptor olefin. Second, we will discuss the use of secondary a-deuterium kinetic isotope effects (DKie) in mechanistic studies of the addition of Br2 to various deuterated cyclohexenes 2,2. Finally, we will explore the possibility of whether a bromonium ion, generated in solution from the solvolysis of traAU -2-bromo-l-[(trifluoromethanesulfonyl)oxy]cyclohexane 4, can be captured by Br on the Br+ of the bromonium ion, thereby generating olefin and Br2. This process would be... 

In addition to the magnetic differences between the deuteron and proton, however, their mass difference may also cause observable effects. A well known example is found in the theory of chemical reactions, where the so called kinetic isotope effects (KIE s) are an important source of information about reaction mechanisms. Also in the field of ESR, such effects may arise, although these have been much less studied than the KIE s. 

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. 

Transition state theory has been useful in providing a rationale for the so-called kinetic isotope effect. The kinetic isotope effect is used by enzy-mologists to probe various aspects of mechanism. Importantly, measured kinetic isotope effects have also been used to monitor if non-classical behaviour is a feature of enzyme-catalysed hydrogen transfer reactions. The kinetic isotope effect arises because of the differential reactivity of, for example, a C-H (protium), a C-D (deuterium) and a C-T (tritium) bond. 

The kinetic parameters are E = 6.3 kcal.mole" and AS = —38.4 eu, and at 25 °C the reaction exhibits a primary kinetic isotope effect of 6.6. When 0-labelled MnO was employed, no labelled oxygen appeared in the benzophenone. The mechanism involves abstraction of hydrogen, either as a hydride ion or a hydrogen atom, from the anion of the alcohol... 

Kemp and Waters found a primary kinetic isotope effect of 8.7 for oxidation of C-deuterated mandelic acid and noted a large difference in rate between the oxidations of mandelic acid k at 24.4 °C = 1.7 l.mole . sec ) and a-hydroxy-isobutyric acid ( 2 at 24.4 °C = 5.6 x 10 l.mole . sec ) — a difference not reproduced for the oxidation of these compounds by the one-equivalent reagent, manganic sulphate. The various data are fully in accord with a Westheimer-type mechanism, viz. 

Typical non-enolising aldehydes are formaldehyde and benzaldehyde, which are oxidised by Co(III) Ce(IV) perchlorate and sulphate , and Mn(III) . The main kinetic features and the primary kinetic isotope effects are the same as for the analogous cyclohexanol oxidations (section 4.3.5) and it is highly probable that the same general mechanism operates. kif olko20 for Co(III) oxidation of formaldehyde is 1.81 (ref. 141), a value in agreement with the observed acid-retardation, i.e. not in accordance with abstraction of a hydroxylic hydrogen atom from H2C(OH)2-The V(V) perchlorate oxidations of formaldehyde and chloral hydrate display an unusual rate expression, viz. 

The oxidations of formic acid by Co(III) and V(V) are straightforward, being first-order with respect to both oxidant and substrate and acid-inverse and slightly acid-catalysed respectively. The primary kinetic isotope effects are l.Sj (25°C)forCo(IU)and4.1 (61.5 C°)for V(V). The low value for Co(lII) is analogous to those for Co(IIl) oxidations of secondary alcohols, formaldehyde and m-nitrobenzaldehyde vide supra). A djo/ h20 for the Co(III) oxidation is about 1.0, which is curiously high for an acid-inverse reaction . The mechanisms clearly parallel those for oxidation of alcohols (p. 376) where Rj and R2 become doubly bonded oxygen. 

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