Kinetic isotope effect types

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. 

If the proton is not equidistant between A and B, it will undergo some movement in the symmetric stretching vibration. Isotopic substitution will, therefore, result in a change in transition state vibrational frequency, with the result that there will be a zero-point energy difference in the transition state. This will reduce the kinetic isotope effect below its maximal possible value. For this type of reaction, therefore, should be a maximum when the proton is midway between A and B in the transition state and should decrease as H lies closer to A or to B. 

Brown and McDonald (1966) provided another type of kinetic evidence for these size relationships by determining secondary kinetic isotope effects in reactions of pyridine-4-pyridines with alkyl iodides. For example, the isotopic rate ratio in the reaction between 4-(methyl-d3)-pyridine and methyl iodide at 25-0 C in nitrobenzene solution was determined to be kjyfk = l-OOl, while that in the corresponding reaction with 2,6-(dimethyl-d6)-pyridine was 1-095. (Brown and McDonald (1966) estimate an uncertainty of 1% in the k jk values.) Furthermore, the isotopic rate ratio in the case of the 2-(methyl-d3)-compound increased from 1 030 to 1-073 as the alkyl group in the alkyl iodide was changed from methyl to isopropyl, i.e. the isotope effect increased with increasing steric requirements of the alkyl iodide. 

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. 

One-step hydroxylation of aromatic nucleus with nitrous oxide (N2O) is among recently discovered organic reactions. A high eflSciency of FeZSM-5 zeolites in this reaction relates to a pronounced biomimetic-type activity of iron complexes stabilized in ZSM-5 matrix. N2O decomposition on these complexes produces particular atomic oj gen form (a-oxygen), whose chemistry is similar to that performed by the active oxygen of enzyme monooxygenases. Room temperature oxidation reactions of a-oxygen as well as the data on the kinetic isotope effect and Moessbauer spectroscopy show FeZSM-5 zeolite to be a successfiil biomimetic model. 

Co2(CO)q system, reveals that the reactions proceed through mononuclear transition states and intermediates, many of which have established precedents. The major pathway requires neither radical intermediates nor free formaldehyde. The observed rate laws, product distributions, kinetic isotope effects, solvent effects, and thermochemical parameters are accounted for by the proposed mechanistic scheme. Significant support of the proposed scheme at every crucial step is provided by a new type of semi-empirical molecular-orbital calculation which is parameterized via known bond-dissociation energies. The results may serve as a starting point for more detailed calculations. Generalization to other transition-metal catalyzed systems is not yet possible. 

The crystal structure of an isopropylamine complex of Ru of this type has been reported [78]. Surprisingly, a negligible kinetic isotope effect (kRuHOH/kRUDOD= 1.05 0.14) was found when D labels on both the OH and RuH sites were used,... 

A secondary deuterium kinetic isotope effect is observed when substitution of a deuterium atom(s) for a hydrogen atom(s) in the substrate changes the rate constant but the bond to the deuterium atom is neither broken nor formed in the transition state of the rate-determining step of the reaction. Several types of secondary hydrogen-deuterium (deuterium) KIEs are found. They are characterized by the position of the deuterium relative to the reaction centre. Thus, a secondary a-deuterium KIE is observed when an a-hydrogen(s) is replaced by deuterium [equations (1) and (2)], where L is either hydrogen or deuterium. 

III. USING KINETIC ISOTOPE EFFECTS TO ELUCIDATE THE MECHANISM OF BENZIDINE-TYPE REARRANGEMENTS OF AMINES... 

Rhee and Shine39 used an impressive combination of nitrogen and carbon kinetic isotope effects to demonstrate that a quinonoidal-type intermediate is formed in the rate-determining step of the acid-catalyzed disproportionation reaction of 4,4 -dichlorohydrazobenzene (equation 26). When the reaction was carried out at 0°C in 60% aqueous dioxane that was 0.5 M in perchloric acid and 0.5 M in lithium perchlorate, extensive product analyses indicated that the major pathway was the disproportionation reaction. In fact, the disproportionation reaction accounted for approximately 72% of the product (compounds 6 and 7) while approximately 13% went to the ortho-semidine (8) and approximately 15% was consumed in the para-semidine (9) rearrangement. 

The most recent addition to Shine s extensive study of the benzidine-type rearrangements41 involved remeasuring the nitrogen and the carbon-13 and carbon-14 kinetic isotope effects at the 4- and at the 4- and 4 -carbons as well as determining the carbon-13 and carbon-14 isotope effects at the 1- and at the 1- and l -carbons in the benzidine rearrangement of hydrazobenzene (equation 30). The reaction, which was carried out in 75% aqueous ethanol that was 0.1 M in hydrochloric acid and 0.3 M in lithium chloride at 0°C, gave an 86% yield of benzidine (11) and a 14% yield of diphenyline (12). The kinetic isotope effects found for the formation of benzidine and diphenyline under these reaction conditions are presented in Table 5. 

The first report of this new type of kinetic isotope effect in a Menshutkin reaction was published by Matsson and coworkers in 198744. In this study, the alpha carbon kll/ku kinetic isotope effect was measured for the Menshutkin reaction between N,N-dimethyl-para-toluidine and labelled methyl iodide in methanol at 30 °C (equation 35). The carbon-11 labelled methyl iodide required for this study was prepared from the nC atoms produced in the cyclotron in three steps45 (equation 37). 

Finally, it is worth noting that the substituent effects are different on the two types of Menshutkin reactions as well. For the benzyl substrates, changing to a better nucleophile, i.e. changing the substituent on the nucleophile from the meta-nitro to a para-methoxy substituent, leads to a later, more product-like transition state with more inverse secondary incoming nucleophile deuterium kinetic isotope effects. Flowever, the same change in nucleophile in the reactions with the methyl and ethyl substrates leads to an earlier transition state and less inverse secondary incoming nucleophile deuterium kinetic isotope effects. 

The review is divided into sections according to the type of metal hydride for convenience in discussing the information systematically. At one extreme, kinetic studies have been performed with many types of silicon hydrides, and much of the data can be interpreted in terms of the electronic properties of the silanes imparted by substituents. At the other extreme, kinetic studies of tin hydrides are limited to a few stannanes, but the rate constants of reactions of a wide range of radical types with the archetypal tin hydride, tributylstannane, are available. Kinetic isotope effects for the various hydrides are collected in a short section, and this is followed by a section that compares the kinetics of reactions of silicon, germanium, and tin hydrides. 

The reaction rate is half-order in palladium and dimeric hydroxides of the type shown are very common for palladium. The reaction is first order in alcohol and a kinetic isotope effect was found for CH2 versus CD2 containing alcohols at 100 °C (1.4-2.1) showing that probably the (3-hydride elimination is rate-determining. Thus, fast pre-equilibria are involved with the dimer as the resting state. When terminal alkenes are present, Wacker oxidation of the alkene is the fastest reaction. Aldehydes are prone to autoxidation and it was found that radical scavengers such as TEMPO suppressed the side reactions and led to an increase of the selectivity [18],... 

Kinetic isotope effect studies have contributed greatly to our understanding of the details of C-H activation by these types of metal complexes. The simplest energy scheme for kinetic isotope effects is presented schematically in Figure 19.7. 

Abstract This chapter describes a number of examples of kinetic isotope effects on chemical reactions of different types (simple gas phase reactions, Sn2 and E reactions in solution and in the gas phase, a and 3 secondary isotope effects, etc.). These examples are used to illustrate many aspects of the measurement, interpretation, and theoretical calculation of KIE s. The chapter concludes with an example of an harmonic semiclassical calculation of a kinetic isotope effect. 

The reactions of A-phenyl a-r-butyl nitrone (PEN) with maleimides, maleic anhydride, and diethyl maleate have been studied by EPR and two types of spin adduct detected. They arise from the reductive addition of PEN to the alkenes and the degradation product of DEN (2-methyl-2-nitropropane). The deuterium and muonium kinetic isotope effects for the addition of the hydrogen atom to a variety of alkenes have been determined experimentally and theoretically. ... 

Human type II inosine monophosphate dehydrogenase catalyses NAD-dependent conversion of inosine monophosphate (IMP) into xanthosine monophosphate (XMP) measurements of the primary kinetic isotope effect using [ H]IMP suggest that both substrates (IMP and NAD) can dissociate from the enzyme-substrate complex therefore, the kinetic mechanism is not ordered. NMR studies indicate hydride transfer to the B or pro-S face of the nicotinamide ring of NAD, while kinetic studies suggest... 

Recently, detailed kinetic studies of the hybrid[type II , 02 - type RH] photo-oxidations of cyclohexane and cyclohexane-dn in both NaY and BaY have been reported. A kinetic isotope effect kulko of 5.7 was determined for X > 400 nm in BaY. This substantial isotope effect, which is nearly identical to the isotope effect on the kinetic acidity of cyclohexane, requires that the proton abstraction step, k, in the alkane radical cation superoxide ion pair be smaller than the back-electron transfer, k, to regenerate the charge-transfer complex (Fig. 18). If kpT were larger than k, the rate expression, Eq. (A) in Fig. 18, would be reduced to Eq. (B) and only a small isotope effect on et would be anticipated. 

Timelines can also be portrayed in charts or figures, as illustrated in excerpt 14D. In fact, charts and figures represent excellent ways to illustrate how smaller, individual projects contribute to larger research goals and how smaller projects complement one another and overlap in time. (Note In excerpt 14D, Kohen uses the following abbreviations in his chart, each defined previously in the proposal hydrogen (H), tritium (T), deuterium (D), kinetic isotope effect (KIE), dihydrofolate reductase (a relatively small protein) (DHFR), and wild type (WT).)... 

These results, as well as rate studies " and kinetic isotope effects ", support a concerted, 5ptra-structured oxenoid-type transition state for the CH oxidations". The original oxygen-rebound mechanism has been discounted (see the computational work in Section I.D). Recently, however, the stepwise radical mechanism was revived in terms of the so-called molecule-induced homolysis , but such radical-type reactivity was severely criticized on the basis of experimental" and theoretical grounds. 

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