Primary deuterium isotope effects

If a protium/tritium (H/T) primary isotope effect is measured with protium at the secondary position ( hh/ th) nd a D/T primary isotope effect with deuterium at the secondary position (feDo/ TD) then a complicated situation ensues. If both primary isotope effects had been measured with protium at the secondary position, then... 

Labels Stereochemistry and Chirality Kinetics Solvent Effects Substituent Effects Primary Deuterium Isotope Effects Barrier Data... 

With very few exceptions, the final step in the nitration mechanism, the deprotonation of the CT complex, is fast and has no effect on the observed kinetics. The fast deprotonation can be confirmed by the absence of an isotope effect when deuterium or tritium is introduced at the substitution site. Several compounds such as benzene, toluene, bromobenzene, and fiuorobenzene were subjected to this test and did not exhibit isotope effects during nitrationThe only case where a primary isotope effect has been seen is with 1,3,5-tri-r-butylbenzene, where steric hindrance evidently makes deprotonation the slow step. ... 

Supporting evidence against irreversible intermediate formation is found in some unpublished studies by H. G. Vilhuber (i5), E. Werstiuk (16), and V. Chuang (3) on the primary deuterium isotope effect. Primary isotope effects of 1.2 to 2.1 were determined for deuterated olefins 34-36,... 

In a number of different kinds of neighboring group processes, deuterium isotope effects have proven useful in providing information about the transition state of the rate-determining step. There are several kinds of isotope effects that can be studied they are solvent isotope effects, primary isotope effects, and secondary isotope effects. Of these types, primary and secondary isotope effects are of more general importance in the study of neighboring group effects. 

Deuterium exchange with the solvent does occur during the reaction, but at a rather slow rate. A symmetrical reaction intermediate must exist, since the rate of incorporation of tritium from the solvent into D-madelate as the substrate yields equimolar amounts of D-and L-product [50]. Thus the data are consistent with the formation of an a-carbanion intermediate with an enzymatic base group acting as the proton acceptor [50]. The proton transfer has to be rate-limiting, as indicated by the approximately 5-fold primary isotope effect for deuterium. In the enzyme-substrate complex, the epimerization occurs with a rate constant of the order of 10 s ... 

Kinetic isotope effects primary and secondary deuterium kinetic isotope effects. Heavy atom isotope effects. Solvent isotope effects. SnI and Sn2 mechanisms. 

The lighter the element, the larger is the ratio of the heavy and the light isotope masses. Thus, the ratio of deuterium and hydrogen masses is 2/1, and that of sulfur-34 and sulfur-32 is 34/32 = 1.0625. This is why the primary kinetic isotope effect of deuterium is relatively high compared to that of sul-fur-34. Consequently, the lowering of the zero-point energies is... 

These are most often deuterium isotope effects, - A(D) meaning that both and (often called D) resonances are observed and subtracted to give the isotope effects. Primary isotope effects on chemical shifts can again be divided into intrinsic and equilibrium isotope effects. The intrinsic ones are observed in systems like... 

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. 

Fig. 4.9. DifiBoing zero-point energies ofprotium- and deuterium-substituted molecules as the cause of primary kinetic isotope effects.

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. 

Table 6-5. Calculated Hydrogen/Deuterium Primary Kinetic Isotope Effects" ...

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. 

Secondly, it has been found that the benzidine rearrangement is subject to a solvent isotope effect d2o/ h2o > 1- If a proton is transferred from the solvent to the substrate in a rate-determining step the substitution of protium by deuterium will lead to a retardation in the rate of reaction (primary isotope effect) whereas if a proton is transferred in a fast equilibrium step preceeding the rate-determining step as in... 

Calculated primary kinetic isotope effects for hydrogen/deuterium at 298 K... 

Deuterium isotope effects have been found even where it is certain that the C—H bond does not break at all in the reaction. Such effects are called secondary isotope effectsf" the term primary isotope effect being reserved for the type discussed previously. Secondary isotope effects can be divided into a and P effects. In a P secondary isotope effect, substitution of deuterium for hydrogen p to the position of bond breaking slows the reaction. An example is solvolysis of isopropyl bromide ... 

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 oxidation by Cr(VI) of aliphatic hydrocarbons containing a tertiary carbon atom has been studied by several groups of workers. Sager and Bradley showed that oxidation of triethylmethane yields triethylcarbinol as the primary product with a primary kinetic isotope effect of about 1.6 (later corrected by Wiberg and Foster to 3.1) for deuterium substitution at the tertiary C-H bond. Oxidations... 

The effect of solvent upon k2 has been reported , and it was concluded that the activated complex is not sufficiently polar to be called ionic . The oxidations of toluene and triphenylmethane exhibit primary kinetic deuterium isotope effects of 2.4 and ca. 4 respectively. No isotopic mixing occurred during formation of the Etard complex from a mixture of normal and deuterated o-nitrotoluene . The chromyl chloride oxidation of a series of substituted diphenylmethanes revealed that electron-withdrawing substituents slow reaction while electronreleasing groups have the opposite effect, the values ofp andp being —2.28 + 0.08 and —2.20 + 0.07 respectively . ... 

The first term was found to correspond to the rate of enolisation (measured by an NMR study of hydrogen-deuterium exchange at the methylene group). The second term predominates at [Cu(II)] > 10 M and is characterised by a primary kinetic isotope effect of 7.4 (25 °C) and a p value of 1.24. Addition of 2,2 -bipridyl (bipy) caused an increase in 2 up to a bipy Cu(II) ratio of 1 1 but at ratios greater than this 2 fell gradually until the enolisation term dominated. The oxidation of a-methoxyacetophenone is much slower but gives a similar rate... 

An important piece of evidence for this mechanism is the fact that a primary isotope effect is observed when the a-hydrogen is replaced by deuterium.2 The Cr(IV) that is produced in the initial step is not stable and is capable of a further oxidation. It is believed that Cr(IV) is reduced to Cr(II), which is then oxidized by Cr(VI) generating Cr(V). This mechanism accounts for the overall stoichiometry of the reaction.3... 

These experiments demonstrate the importance of proton transfer processes during hole transfer through DNA. S. Steenken has already remarked that a proton shift between the G C bases stabilizes the positive charge [23]. If such a proton shift is coupled with the hole shift, a deuterium isotope effect should arise. Actually, H/D isotope effects are described by V. Shafiro-vich, M.D. Sevilla as well as H.H. Thorp in their articles of this volume. Experiments with our assay [22] also demonstrate (Fig. 16) that hole transfer in protonated DNA (H20 as solvent) is three times more efficient than in deuterated DNA (D20 as solvent). If this reflects a primary isotope effect, it shows that the charge transfer is coupled with a proton transfer. 

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